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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Posted in BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Biological Networks, Gene Regulation and Evolution, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Screening, Gene Regulation and Evolution, Genetics & Innovations in Treatment, Genome Biology, Genomic Expression, Genomic Testing: Methodology for Diagnosis, interventional oncology, Variation in human protein-coding regions, tagged AACR, American Association for Cancer Research, breast cancer, Cancer Genomics, cancer genomics and therapy, cancer metastasis, Clonal evolution, Curation, curation communities, Glioma, gliomas, mutational burden, mutational spectrum, myeloid dysplatic syndrome, myeloma, spliceosome, tumor heterogeneity on April 28, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Reporter: Stephen J. Williams, PhD

Minisymposium: Evaluating Cancer Genomics from Normal Tissues through Evolution to Metastatic Disease

Oncologic therapy shapes the fitness landscape of clonal hematopoiesis

April 28, 2020, 4:10 PM – 4:20 PM

Presenter/Authors
Kelly L. Bolton, Ryan N. Ptashkin, Teng Gao, Lior Braunstein, Sean M. Devlin, Minal Patel, Antonin Berthon, Aijazuddin Syed, Mariko Yabe, Catherine Coombs, Nicole M. Caltabellotta, Mike Walsh, Ken Offit, Zsofia Stadler, Choonsik Lee, Paul Pharoah, Konrad H. Stopsack, Barbara Spitzer, Simon Mantha, James Fagin, Laura Boucai, Christopher J. Gibson, Benjamin Ebert, Andrew L. Young, Todd Druley, Koichi Takahashi, Nancy Gillis, Markus Ball, Eric Padron, David Hyman, Jose Baselga, Larry Norton, Stuart Gardos, Virginia Klimek, Howard Scher, Dean Bajorin, Eder Paraiso, Ryma Benayed, Maria Arcilla, Marc Ladanyi, David Solit, Michael Berger, Martin Tallman, Montserrat Garcia-Closas, Nilanjan Chatterjee, Luis Diaz, Ross Levine, Lindsay Morton, Ahmet Zehir, Elli Papaemmanuil. Memorial Sloan Kettering Cancer Center, New York, NY, University of North Carolina at Chapel Hill, Chapel Hill, NC, University of Cambridge, Cambridge, United Kingdom, Dana-Farber Cancer Institute, Boston, MA, Washington University, St Louis, MO, The University of Texas MD Anderson Cancer Center, Houston, TX, Moffitt Cancer Center, Tampa, FL, National Cancer Institute, Bethesda, MD

Abstract
Recent studies among healthy individuals show evidence of somatic mutations in leukemia-associated genes, referred to as clonal hematopoiesis (CH). To determine the relationship between CH and oncologic therapy we collected sequential blood samples from 525 cancer patients (median sampling interval time = 23 months, range: 6-53 months) of whom 61% received cytotoxic therapy or external beam radiation therapy and 39% received either targeted/immunotherapy or were untreated. Samples were sequenced using deep targeted capture-based platforms. To determine whether CH mutational features were associated with tMN risk, we performed Cox proportional hazards regression on 9,549 cancer patients exposed to oncologic therapy of whom 75 cases developed tMN (median time to transformation=26 months). To further compare the genetic and clonal relationships between tMN and the proceeding CH, we analyzed 35 cases for which paired samples were available. We compared the growth rate of the variant allele fraction (VAF) of CH clones across treatment modalities and in untreated patients. A significant increase in the growth rate of CH mutations was seen in DDR genes among those receiving cytotoxic (p=0.03) or radiation therapy (p=0.02) during the follow-up period compared to patients who did not receive therapy. Similar growth rates among treated and untreated patients were seen for non-DDR CH genes such as DNMT3A. Increasing cumulative exposure to cytotoxic therapy (p=0.01) and external beam radiation therapy (2×10-8) resulted in higher growth rates for DDR CH mutations. Among 34 subjects with at least two CH mutations in which one mutation was in a DDR gene and one in a non-DDR gene, we studied competing clonal dynamics for multiple gene mutations within the same patient. The risk of tMN was positively associated with CH in a known myeloid neoplasm driver mutation (HR=6.9, p<10-6), and increased with the total number of mutations and clone size. The strongest associations were observed for mutations in TP53 and for CH with mutations in spliceosome genes (SRSF2, U2AF1 and SF3B1). Lower hemoglobin, lower platelet counts, lower neutrophil counts, higher red cell distribution width and higher mean corpuscular volume were all positively associated with increased tMN risk. Among 35 cases for which paired samples were available, in 19 patients (59%), we found evidence of at least one of these mutations at the time of pre-tMN sequencing and in 13 (41%), we identified two or more in the pre-tMN sample. In all cases the dominant clone at tMN transformation was defined by a mutation seen at CH Our serial sampling data provide clear evidence that oncologic therapy strongly selects for clones with mutations in the DDR genes and that these clones have limited competitive fitness, in the absence of cytotoxic or radiation therapy. We further validate the relevance of CH as a predictor and precursor of tMN in cancer patients. We show that CH mutations detected prior to tMN diagnosis were consistently part of the dominant clone at tMN diagnosis and demonstrate that oncologic therapy directly promotes clones with mutations in genes associated with chemo-resistant disease such as TP53.

therapy resulted also in clonal evolution and saw changes in splice variants and spliceosome
therapy promotes current DDR mutations
clonal hematopoeisis due to selective pressures
mutations, variants number all predictive of myeloid disease
deferring adjuvant therapy for breast cancer patients with patients in highest MDS risk group based on biomarkers, greatly reduced their risk for MDS

5704 – Pan-cancer genomic characterization of patient-matched primary, extracranial, and brain metastases

Presenter/AuthorsOlivia W. Lee, Akash Mitra, Won-Chul Lee, Kazutaka Fukumura, Hannah Beird, Miles Andrews, Grant Fischer, John N. Weinstein, Michael A. Davies, Jason Huse, P. Andrew Futreal. The University of Texas MD Anderson Cancer Center, TX, The University of Texas MD Anderson Cancer Center, TX, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, AustraliaDisclosures O.W. Lee: None. A. Mitra: None. W. Lee: None. K. Fukumura: None. H. Beird: None. M. Andrews: ; Merck Sharp and Dohme. G. Fischer: None. J.N. Weinstein: None. M.A. Davies: ; Bristol-Myers Squibb. ; Novartis. ; Array BioPharma. ; Roche and Genentech. ; GlaxoSmithKline. ; Sanofi-Aventis. ; AstraZeneca. ; Myriad Genetics. ; Oncothyreon. J. Huse: None. P. Futreal: None.

Abstract: Brain metastases (BM) occur in 10-30% of patients with cancer. Approximately 200,000 new cases of brain metastases are diagnosed in the United States annually, with median survival after diagnosis ranging from 3 to 27 months. Recently, studies have identified significant genetic differences between BM and their corresponding primary tumors. It has been shown that BM harbor clinically actionable mutations that are distinct from those in the primary tumor samples. Additional genomic profiling of BM will provide deeper understanding of the pathogenesis of BM and suggest new therapeutic approaches.
We performed whole-exome sequencing of BM and matched tumors from 41 patients collected from renal cell carcinoma (RCC), breast cancer, lung cancer, and melanoma, which are known to be more likely to develop BM. We profiled total 126 fresh-frozen tumor samples and performed subsequent analyses of BM in comparison to paired primary tumor and extracranial metastases (ECM). We found that lung cancer shared the largest number of mutations between BM and matched tumors (83%), followed by melanoma (74%), RCC (51%), and Breast (26%), indicating that cancer type with high tumor mutational burden share more mutations with BM. Mutational signatures displayed limited differences, suggesting a lack of mutagenic processes specific to BM. However, point-mutation heterogeneity revealed that BM evolve separately into different subclones from their paired tumors regardless of cancer type, and some cancer driver genes were found in BM-specific subclones. These models and findings suggest that these driver genes may drive prometastatic subclones that lead to BM. 32 curated cancer gene mutations were detected and 71% of them were shared between BM and primary tumors or ECM. 29% of mutations were specific to BM, implying that BM often accumulate additional cancer gene mutations that are not present in primary tumors or ECM. Co-mutation analysis revealed a high frequency of TP53 nonsense mutation in BM, mostly in the DNA binding domain, suggesting TP53 nonsense mutation as a possible prerequisite for the development of BM. Copy number alteration analysis showed statistically significant differences between BM and their paired tumor samples in each cancer type (Wilcoxon test, p < 0.0385 for all). Both copy number gains and losses were consistently higher in BM for breast cancer (Wilcoxon test, p =1.307e-5) and lung cancer (Wilcoxon test, p =1.942e-5), implying greater genomic instability during the evolution of BM.
Our findings highlight that there are more unique mutations in BM, with significantly higher copy number alterations and tumor mutational burden. These genomic analyses could provide an opportunity for more reliable diagnostic decision-making, and these findings will be further tested with additional transcriptomic and epigenetic profiling for better characterization of BM-specific tumor microenvironments.

are there genomic signatures different in brain mets versus non metastatic or normal?
32 genes from curated databases were different between brain mets and primary tumor
frequent nonsense mutations in TP53
divergent clonal evolution of drivers in BMets from primary
they were able to match BM with other mutational signatures like smokers and lung cancer signatures

5707 – A standard operating procedure for the interpretation of oncogenicity/pathogenicity of somatic mutations

Presenter/AuthorsPeter Horak, Malachi Griffith, Arpad Danos, Beth A. Pitel, Subha Madhavan, Xuelu Liu, Jennifer Lee, Gordana Raca, Shirley Li, Alex H. Wagner, Shashikant Kulkarni, Obi L. Griffith, Debyani Chakravarty, Dmitriy Sonkin. National Center for Tumor Diseases, Heidelberg, Germany, Washington University School of Medicine, St. Louis, MO, Mayo Clinic, Rochester, MN, Georgetown University Medical Center, Washington, DC, Dana-Farber Cancer Institute, Boston, MA, Frederick National Laboratory for Cancer Research, Rockville, MD, University of Southern California, Los Angeles, CA, Sunquest, Boston, MA, Baylor College of Medicine, Houston, TX, Memorial Sloan Kettering Cancer Center, New York, NY, National Cancer Institute, Rockville, MDDisclosures P. Horak: None. M. Griffith: None. A. Danos: None. B.A. Pitel: None. S. Madhavan: ; Perthera Inc. X. Liu: None. J. Lee: None. G. Raca: None. S. Li: ; Sunquest Information Systems, Inc. A.H. Wagner: None. S. Kulkarni: ; Baylor Genetics. O.L. Griffith: None. D. Chakravarty: None. D. Sonkin: None.AbstractSomatic variants in cancer-relevant genes are interpreted from multiple partially overlapping perspectives. When considered in discovery and translational research endeavors, it is important to determine if a particular variant observed in a gene of interest is oncogenic/pathogenic or not, as such knowledge provides the foundation on which targeted cancer treatment research is based. In contrast, clinical applications are dominated by diagnostic, prognostic, or therapeutic interpretations which in part also depends on underlying variant oncogenicity/pathogenicity. The Association for Molecular Pathology, the American Society of Clinical Oncology, and the College of American Pathologists (AMP/ASCO/CAP) have published structured somatic variant clinical interpretation guidelines which specifically address diagnostic, prognostic, and therapeutic implications. These guidelines have been well-received by the oncology community. Many variant knowledgebases, clinical laboratories/centers have adopted or are in the process of adopting these guidelines. The AMP/ASCO/CAP guidelines also describe different data types which are used to determine oncogenicity/pathogenicity of a variant, such as: population frequency, functional data, computational predictions, segregation, and somatic frequency. A second collaborative effort created the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets to provide a harmonized vocabulary that provides an evidence-based ranking system of molecular targets that supports their value as clinical targets. However, neither of these clinical guideline systems provide systematic and comprehensive procedures for aggregating population frequency, functional data, computational predictions, segregation, and somatic frequency to consistently interpret variant oncogenicity/pathogenicity, as has been published in the ACMG/AMP guidelines for interpretation of pathogenicity of germline variants. In order to address this unmet need for somatic variant oncogenicity/pathogenicity interpretation procedures, the Variant Interpretation for Cancer Consortium (VICC, a GA4GH driver project) Knowledge Curation and Interpretation Standards (KCIS) working group (WG) has developed a Standard Operating Procedure (SOP) with contributions from members of ClinGen Somatic Clinical Domain WG, and ClinGen Somatic/Germline variant curation WG using an approach similar to the ACMG/AMP germline pathogenicity guidelines to categorize evidence of oncogenicity/pathogenicity as very strong, strong, moderate or supporting. This SOP enables consistent and comprehensive assessment of oncogenicity/pathogenicity of somatic variants and latest version of an SOP can be found at https://cancervariants.org/wg/kcis/.

best to use this SOP for somatic mutations and not rearangements
variants based on oncogenicity as strong to weak
useful variant knowledge on pathogenicity curated from known databases
the recommendations would provide some guideline on curating unknown somatic variants versus known variants of hereditary diseases
they have not curated RB1 mutations or variants (or for other RBs like RB2? p130?)

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM

Posted in Cancer - General, Cancer and Current Therapeutics, Conference Coverage with Social Media, DNA repair, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, Scientific & Biotech Conferences: Press Coverage, Ubiquitin, tagged AACR, American Association for Cancer Research, anti-cancer therapeutics, cancer chemotherapy, Cancer Drug Discovery, DNA replication, DNA-damage response, Drug development, Drug discovery, MTHD2, replication stress, retinoblastoma gene, skp2, synthetic lethal screen, ubiquitin-proteosome on April 28, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM

Reporter: Stephen J. Williams, PhD

Updated on 07/08/2021

https://cancerdiscovery.aacrjournals.org/content/early/2021/07/01/2159-8290.CD-20-1741

Session VMS.ET04.01 – Novel Targets and Therapies

Targeting chromatin remodeling-associated genetic vulnerabilities in cancer: PBRM1 defects are synthetic lethal with PARP and ATR inhibitors

Presenter/AuthorsRoman Merial Chabanon, Daphné Morel, Léo Colmet-Daage, Thomas Eychenne, Nicolas Dorvault, Ilirjana Bajrami, Marlène Garrido, Suzanna Hopkins, Cornelia Meisenberg, Andrew Lamb, Theo Roumeliotis, Samuel Jouny, Clémence Astier, Asha Konde, Geneviève Almouzni, Jyoti Choudhary, Jean-Charles Soria, Jessica Downs, Christopher J. Lord, Sophie Postel-Vinay. Gustave Roussy, Villejuif, France, The Francis Crick Institute, London, United Kingdom, Institute of Cancer Research, London, United Kingdom, Sage Bionetworks, Seattle, WA, Institute of Cancer Research, London, United Kingdom, Institute of Cancer Research, London, United Kingdom, Institut Curie, Paris, France, Université Paris-Sud/Université Paris-Saclay, Le Kremlin-Bicêtre, France, Gustave Roussy Cancer Campus and U981 INSERM, ATIP-Avenir group, Villejuif, FranceDisclosures R.M. Chabanon: None. D. Morel: None. L. Colmet-Daage: None. T. Eychenne: None. N. Dorvault: None. I. Bajrami: None. M. Garrido: None. S. Hopkins: ; Fishawack Group of Companies. C. Meisenberg: None. A. Lamb: None. T. Roumeliotis: None. S. Jouny: None. C. Astier: None. A. Konde: None. G. Almouzni: None. J. Choudhary: None. J. Soria: ; Medimmune/AstraZeneca. ; Astex. ; Gritstone. ; Clovis. ; GSK. ; GamaMabs. ; Lilly. ; MSD. ; Mission Therapeutics. ; Merus. ; Pfizer. ; PharmaMar. ; Pierre Fabre. ; Roche/Genentech. ; Sanofi. ; Servier. ; Symphogen. ; Takeda. J. Downs: None. C.J. Lord: ; AstraZeneca. ; Merck KGaA. ; Artios. ; Tango. ; Sun Pharma. ; GLG. ; Vertex. ; Ono Pharma. ; Third Rock Ventures. S. Postel-Vinay: ; Merck KGaA. ; Principal investigator of clinical trials for Gustave Roussy.; Boehringer Ingelheim. ; Principal investigator of clinical trials for Gustave Roussy.; Roche. ; Principal investigator of clinical trials for Gustave Roussy. Benefited from reimbursement for attending symposia.; AstraZeneca. ; Principal investigator of clinical trials for Gustave Roussy.; Clovis. ; Principal investigator of clinical trials for Gustave Roussy.; Bristol-Myers Squibb. ; Principal investigator of clinical trials for Gustave Roussy.; Agios. ; Principal investigator of clinical trials for Gustave Roussy.; GSK.AbstractAim: Polybromo-1 (PBRM1), a specific subunit of the pBAF chromatin remodeling complex, is frequently inactivated in cancer. For example, 40% of clear cell Renal Cell Carcinoma (ccRCC) and 15% of cholangiocarcinoma present deleterious PBRM1 mutations. There is currently no precision medicine-based therapeutic approach that targets PBRM1 defects. To identify novel, targeted therapeutic strategies for PBRM1-defective cancers, we carried out high-throughput functional genomics and drug screenings followed by in vitro and in vivo validation studies.
Methods: High-throughput siRNA-drug sensitization and drug sensitivity screens evaluating > 150 cancer-relevant small molecules in dose-response were performed in Pbrm1 siRNA-transfected mouse embryonic stem cells (mES) and isogenic PBRM1-KO or -WT HAP1 cells, respectively. After identification of PBRM1-selective small molecules, revalidation was carried out in a series of in-house-generated isogenic models of PBRM1 deficiency – including 786-O (ccRCC), A498 (ccRCC), U2OS (osteosarcoma) and H1299 (non-small cell lung cancer) human cancer cell lines – and non-isogenic ccRCC models, using multiple clinical compounds. Mechanistic dissection was performed using immunofluorescence, RT-qPCR, western blotting, DNA fiber assay, transcriptomics, proteomics and DRIP-sequencing to evaluate markers of DNA damage response (DDR), replication stress and cell-autonomous innate immune signaling. Preclinical data were integrated with TCGA tumor data.
Results: Parallel high-throughput drug screens independently identified PARP inhibitors (PARPi) as being synthetic lethal with PBRM1 defects – a cell type-independent effect which was exacerbated by ATR inhibitors (ATRi) and which we revalidated in vitro in isogenic and non-isogenic systems and in vivo in a xenograft model. PBRM1 defects were associated with increased replication fork stress (higher γH2AX and RPA foci levels, decreased replication fork speed and increased ATM checkpoint activation), R-loop accumulation and enhanced genomic instability in vitro; these effects were exacerbated upon PARPi exposure. In patient tumor samples, we also found that PBRM1-mutant cancers possessed a higher mutational load. Finally, we found that ATRi selectively activated the cGAS/STING cytosolic DNA sensing pathway in PBRM1-deficient cells, resulting in increased expression of type I interferon genes.
Conclusion: PBRM1-defective cancer cells present increased replication fork stress, R-loop formation, genome instability and are selectively sensitive to PARPi and ATRi through a synthetic lethal mechanism that is cell type-independent. Our data provide the pre-clinical rationale for assessing PARPi as a monotherapy or in combination with ATRi or immune-modulating agents in molecularly-selected patients with PBRM1-defective cancers.

1057 – Targeting MTHFD2 using first-in-class inhibitors kills haematological and solid cancer through thymineless-induced replication stress

Presenter/AuthorsThomas Helleday. University of Sheffield, Sheffield, United KingdomDisclosures T. Helleday: None.AbstractSummary
Thymidine synthesis pathways are upregulated pathways in cancer. Since the 1940s, targeting nucleotide and folate metabolism to induce thymineless death has remained first-line anti-cancer treatment. Recent discoveries that showing cancer cells have rewired networks and exploit unique enzymes for proliferation, have renewed interest in metabolic pathways. The cancer-specific expression of MTHFD2 has gained wide-spread attention and here we describe an emerging role for MTHFD2 in the DNA damage response (DDR). The folate metabolism enzyme MTHFD2 is one of the most consistently overexpressed metabolic enzymes in cancer and an emerging anticancer target. We show a novel role for MTHFD2 being essential for DNA replication and genomic stability in cancer cells. We describe first-in-class nanomolar MTHFD2 inhibitors (MTHFD2i), with protein co-crystal structures demonstrating binding in the active site of MTHFD2 and engaging with the target in cells and tumours. We show MTHFD2i reduce replication fork speed and induce replication stress, followed by S phase arrest, apoptosis and killing of a range of haematological and solid cancer cells in vitro and in vivo, with a therapeutic window spanning up to four orders of magnitude compared to non-transformed cells. Mechanistically, MTHFD2i prevent thymidine production leading to mis-incorporation of uracil into DNA and replication stress. As MTHFD2 expression is cancer specific there is a potential of MTHFD2i to synergize with other treatments. Here, we show MTHFD2i synergize with dUTPase inhibitors as well as other DDR inhibitors and demonstrate the mechanism of action. These results demonstrate a new link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically.
Keywords
MTHFD2, one-carbon metabolism, folate metabolism, DNA replication, replication stress, synthetic lethal, thymineless death, small-molecule inhibitor, DNA damage response

1060 – Genetic and pharmacologic inhibition of Skp2, an E3 ubiquitin ligase and RB1-target, has antitumor activity in RB1-deficient human and mouse small cell lung cancer (SCLC)

Presenter/Authors: Hongling Zhao, Vineeth Sukrithan, Niloy Iqbal, Cari Nicholas, Yingjiao Xue, Joseph Locker, Juntao Zou, Liang Zhu, Edward L. Schwartz. Albert Einstein College of Medicine, Bronx, NY, Albert Einstein College of Medicine, Bronx, NY, Albert Einstein College of Medicine, Bronx, NY, University of Pittsburgh Medical Center, Pittsburgh, PA, Albert Einstein College of Medicine, Bronx, NY
Disclosures: H. Zhao: None. V. Sukrithan: None. N. Iqbal: None. C. Nicholas: None. Y. Xue: None. J. Locker: None. J. Zou: None. L. Zhu: None. E.L. Schwartz: None.
Abstract: The identification of driver mutations and their corresponding targeted drugs has led to significant improvements in the treatment of non-small cell lung cancer (NSCLC) and other solid tumors; however, similar advances have not been made in the treatment of small cell lung cancer (SCLC). Due to their aggressive growth, frequent metastases, and resistance to chemotherapy, the five-year overall survival of SCLC is less than 5%. While SCLC tumors can be sensitive to first-line therapy of cisplatin and etoposide, most patients relapse, often in less than 3 months after initial therapy. Dozens of drugs have been tested clinically in SCLC, including more than 40 agents that have failed in phase III trials.
The near uniform bi-allelic inactivation of the tumor suppressor gene RB1 is a defining feature of SCLC. RB1 is mutated in highly aggressive tumors, including SCLC, where its functional loss, along with that of TP53, is both required and sufficient for tumorigenesis. While it is known that RB1 mutant cells fail to arrest at G1/S in response to checkpoint signals, this information has not led to effective strategies to treat RB1-deficient tumors, and it has been challenging to develop targeted drugs for tumors that are driven by the loss of gene function.
Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in Rb1/p53-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, and we confirmed this was the mechanism of protection in the RP-Skp2 KO mice by using the knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind to and/or inhibit Skp2 induced apoptosis and inhibited SCLC cell growth. In a panel of SCLC cell lines, growth inhibition by a Skp2 inhibitor was not correlated with sensitivity/resistance to etoposide. Targeting Skp2 also had in vivo antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using the genetic and pharmacologic approaches, antitumor activity was seen in vivo in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. The identification and validation of an actionable target downstream of RB1 could have a broad impact on treatment of SCLC and other advanced tumors with mutant RB1, for which there are currently no targeted therapies available.

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Early Detection and ctDNA 1:35 – 3:55 PM

Posted in BioBanking, BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Breast Cancer - impalpable breast lesions, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Circulating Tumor Cells (CTC), Computational Biology/Systems and Bioinformatics, interventional oncology, Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood, Scientific & Biotech Conferences: Press Coverage, tagged AACR, American Association for Cancer Research, breast cancer screening, Cancer screening, Clinical trial, Conference Coverage with Social Media, ctDNA, ctDNA Liquid Biopsy, liquid biopsy, real time conference coverage, TRACERx on April 28, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Early Detection and ctDNA 1:35 – 3:55 PM

Reporter: Stephen J. Williams, PhD

Introduction
Alberto Bardelli

circulating tumor DNA has been around but with NGS now we can have more specificity in analyzing ctDNA
interest lately in using liquid biopsy to gain insight on tumor heterogeneity versus single needle biopsy of the solid tumor
these talks will however be on ctDNA as a diagnostic and therapeutic monitoring modality

Prediction of cancer and tissue of origin in individuals with suspicion of cancer using a cell-free DNA multi-cancer early detection test
David Thiel

@MayoClinic

test has a specificity over 90% and intended to used along with guideline
The Circulating Cell-free Genome Atlas Study (clinical trial NCT02889978) (CCGA) study divided into three substudies: highest performing assay, refining assay, validation of assays
methylation based assays worked better than sequencing (bisulfite sequencing)
used a machine learning algorithm to help refine assay
prediction was >90%; subgroup for high clinical suspicion of cancer
HCS sensitivity was 100% and specificity very high; but sensitivity on training set was 40% and results may have been confounded by including kidney cancer
TOO tissue of origin was predicted in greater than 99% in both training and validation sets

A first-of-its-kind prospective study of a multi-cancer blood test to screen and manage 10,000 women with no history of cancer

DETECT-A study: prospective interventional study; can multi blood test be used prospectively and can lead to a personalized care; can the screen be used to complement current therapy?
10,000 women aged 65-75; these women could not have previous cancer and conducted through Geisinger Health Network; multi test detects DNA and protein and standard of care screening
the study focused on safety so a committee was consulted on each case, and used a diagnostic PET-CT
blood test alone not good but combined with protein and CT scans much higher (5 fold increase) detection for breast cancer

Nickolas Papadopoulos

@HopkinsMedicine

Discussant
David Huntsman

there are mutiple opportunities yet at same time there are still challenges to utilize these cell free tests in therapeutic monitoring, diagnostic, and screening however sensitivities for some cancers are still too low to use in large scale screening however can supplement current screening guidelines
we have to ask about false positive rate and need to concentrate on prospective studies
we must consider how tests will be used, population health studies will need to show improved survival

Phylogenetic tracking and minimal residual disease detection using ctDNA in early-stage NSCLC: A lung TRACERx study
Chris Abbosh @ucl

TRACERx study in collaboration with Charles Swanton.
multiplex PCR to track 200 SNVs: correlate tumor tissue biopsy with ctDNA
spike in assay shows very good sensitivity and specificity for SNVs variants tracked, did over 400 TRACERx libraries
sensitivity increases when tracking more variants but specificity does go down a bit
tracking variants can show evidence of subclonal dynamics and evolution and copy number deletion events; they also show neoantigen editing or changing of their neoantigens
this assay can detect low variants in a reproducible manner

The TRACERx (TRAcking Cancer Evolution through therapy (Rx)) lung study is a multi-million pound research project taking place over nine years, which will transform our understanding of non-small cell lung cancer (NSCLC) and take a practical step towards an era of precision medicine. The study will uncover mechanisms of cancer evolution by analysing the intratumour heterogeneity in lung tumours from approximately 850 patients and tracking its evolutionary trajectory from diagnosis through to relapse. At £14 million, it’s the biggest single investment in lung cancer research by Cancer Research UK, and the start of a strategic UK-wide focus on the disease, aimed at making real progress for patients.

Led by Professor Charles Swanton at UCL, the study will bring together a network of experts from different disciplines to help integrate clinical and genomic data and identify patients who could benefit from trials of new, targeted treatments. In addition, it will use a whole suite of cutting edge analytical techniques on these patients’ tumour samples, giving unprecedented insight into the genomic landscape of primary and metastatic tumours and the impact of treatment upon this landscape.

In future, TRACERx will enable us to define how intratumour heterogeneity impacts upon cancer immunity throughout tumour evolution and therapy. Such studies will help define how the clinical evaluation of intratumour heterogeneity can inform patient stratification and the development of combinatorial therapies incorporating conventional, targeted and immune based therapeutics.

Intratumour heterogeneity is increasingly recognised as a major hurdle to achieve improvements in therapeutic outcome and biomarker validation. Intratumour genetic diversity provides a substrate for tumour adaptation and evolution. However, the evolutionary genomic landscape of non-small cell lung cancer (NSCLC) and how it changes through the disease course has not been studied in detail. TRACERx is a prospective observational study with the following objectives:

Primary Objectives

Define the relationship between intratumour heterogeneity and clinical outcome following surgery and adjuvant therapy (including relationships between intratumour heterogeneity and clinical disease stage and histological subtypes of NSCLC).
Establish the impact of adjuvant platinum-containing regimens upon intratumour heterogeneity in relapsed disease compared to primary resected tumour.

Key Secondary Objectives

Develop and validate an intratumour heterogeneity (ITH) ratio index as a prognostic and predictive biomarker in relation to disease-free survival and overall survival.
Infer a complete picture of NSCLC evolutionary dynamics – define drivers of genomic instability, metastatic progression and drug resistance by identifying and tracking the dynamics of somatic mutational heterogeneity, and chromosomal structural and numerical instability present in the primary tumour and at metastatic sites. Individual tumour phylogenetic tree analysis will:
- Establish the order of somatic events in relation to genomic instability onset and metastatic progression
- Decipher genetic “bottlenecking” events following metastasis and drug therapy
- Establish dynamics of tumour evolution during the disease course from early to late stage NSCLC.
Initiate a longitudinal biobank of circulating tumour cells (CTCs) and circulating-free tumour DNA (cfDNA) to develop analytical methods for the early detection and monitoring of tumour evolution over time.
Develop a longitudinal tissue resource to serve as a platform to assess the relationship between genetic intratumour heterogeneity and the host immune response.
Define relationships between intratumour heterogeneity and targeted/cytotoxic therapeutic outcome.
Use a lung cancer specific gene panel in a certified Good Clinical Practice (GCP) laboratory environment to define clonally dominant disease drivers to address the role of clonal driver dominance in targeted therapeutic response and to guide stratification of lung cancer treatment and future clinical study inclusion (paired primary-metastatic site comparisons in at least 270 patients with relapsed disease).

Utility of longitudinal circulating tumor DNA (ctDNA) modeling to predict RECIST-defined progression in first-line patients with epidermal growth factor receptor mutation-positive (EGFRm) advanced non-small cell lung cancer (NSCLC)
Martin Johnson

Impact of the EML4-ALK fusion variant on the efficacy of lorlatinib in patients (pts) with ALK-positive advanced non-small cell lung cancer (NSCLC)
Todd Bauer

From an interview with Dr. Bauer at https://www.lungcancernews.org/2019/08/14/making-headway-with-lorlatinib/

Lorlatinib, a smallmolecule inhibitor of ALK and ROS1, was granted accelerated U.S. Food and Drug Administration approval in November 2018 for patients with ALK-positive metastatic NSCLC whose disease has progressed on crizotinib and at least one other ALK inhibitor or whose disease has progressed on alectinib or ceritinib as the first ALK inhibitor therapy for metastatic disease. Todd M. Bauer, MD, a medical oncologist and senior investigator at Sarah Cannon Research Institute/Tennessee Oncology, PLLC, in Nashville, has been very involved with the development of lorlatinib since the beginning. In the following interview, Dr. Bauer discusses some of lorlatinib’s unique toxicities, as well as his first-hand experiences with the drug.

For further reading: Solomon B, Besse B, Bauer T, et al. Lorlatinib in Patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet. 2018;19(12):P1654-1667.

Abstract

BACKGROUND: Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer.

METHODS: In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1-6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1-5 only), and safety data for all treated patients (EXP1-6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865.

FINDINGS: Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI 73·5-97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66·7%; 95% CI 9·4-99·2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2-5), objective responses were achieved in 93 (47·0%; 39·9-54·2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5-73·4) of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1-80·8) of 59 patients who had only received previous crizotinib (EXP2-3A), nine (32·1%; 15·9-52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6-48·5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4-5). Objective intracranial response was achieved in 20 (87·0%; 95% CI 66·4-97·2) of 23 patients with measurable baseline CNS lesions in EXP2-3A, five (55·6%; 21·2-86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3-67·5) of 49 patients in EXP4-5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3-4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3-4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported.

INTERPRETATION: Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy.

loratinib could be used for crizotanib resistant tumors based on EML4-ALK variants present in ctDNA

Reference:
1. Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs crizotinib (CZ) in untreated advanced ALK+ NSCLC. J Clin Oncol 36, 2018 (suppl; abstr 9043).

Discussion

Corey Langer

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on COVID-19 and Cancer 9:00 AM

Posted in Biomarkers: Inflammation, Cancer - General, Cancer and Current Therapeutics, Cancer Researchers Fighting COVID-19, Coronavirus Gene Expression, COVID-19, COVID-19: Pandemic Surgery Guidance, Economic Impact of Coronavirus Pandemic, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, SAR-Cov-2 a vasculotropic (blood vessels) RNA Virus, SARS-CoV-2, Seasonality & Environmental Factors in Resurgence, Serology tests for coronavirus antibodies, Vaccinology, Viral diseases, Virus Infective Acute Respiratory Syndrome: SARS-CoV, tagged #COVID-19, #COVID19andcancer, AACR, American Association for Cancer Research, Cancer, COVID-19, patient safety, SARS-CoV-2 on April 28, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on COVID-19 and Cancer 9:00 AM

Reporter: Stephen J. Williams, PhD

COVID-19 and Cancer

Introduction

Antoni Ribas
UCLA Medical Center

Almost 60,000 viewed the AACR 2020 Virtual meeting for the April 27 session
The following speakers were the first cancer researchers treating patients at the epicenters of the pandemic even though nothing was known about the virus

The experience of treating patients with cancer during the COVID-19 pandemic in China
Li Zhang, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

reporting a retrospective study from three hospitals from Wuhan
2.2% of Wuhan cancer patients were COVID positive; most were lung cancers and most male; 35% were stage four
most have hospital transmission of secondary infection; had severe events when admitted
74% were prescribed antivirals like ganciclovir and others; iv IgG was given to some
mortailtiy rate of 26%; by April 4 54% were cured and discharged; median time of infection to severe event was 7 days; clinical presentation SARS sepsis, and shock
by day 10 in lung cancer patients, see lung path but after supportive therapy improved
cancer patients at stage four who did not receive therapy were at higher risk
cancer patients who had received chemo in last 14 days had higher risk of infection
they followed up with cancer patients on I/O inhibitors; it seemed there was only one patient that contracted COVID19 so there may not be as much risk with immune checkpoint inhibitors

TERAVOLT (Thoracic cancERs international coVid 19 cOLlaboraTion): First results of a global collaboration to address the impact of COVID-19 in patients with thoracic malignancies

Marina Chiara Garassino

@marinagarassino
Fondazione IRCCS Istituto Nazionale dei Tumori

Dr Marina Chiara Garassino is the Chief of the Thoracic Oncology Unit at Istituto Nazionale dei Tumori, Milan, Italy. She leads the strategy for clinical and translational research in advanced and locally advanced NSCLC, SCLC, mesothelioma and thymic malignancies. Istituto Nazionale dei Tumori in Milan is the most important comprehensive cancer in Italy and one of the most important in Europe. As a medical oncologist, she has done research in precision medicine and in immuno-oncology. Her main research interests have been mainly development of new drugs and therapeutical strategies and biomarkers. She has contributed to over 150 peer-reviewed publications, including publications as first or last author in the New England Journal of Medicine, Lancet Oncology, Journal of Clinical Oncology, Annals of Oncology. She has delivered many presentations at international congresses, including AACR, ASCO, ECCO, ESMO, WCLC. Her education includes a degree and further specialization in Medical Oncology at Università degli Studi in Milan. She achieved a Master Degree in Oncology management at University of Economics “Luigi Bocconi”. She completed her training with an ESMO Clinical fellowship in 2009 at Christie’s Hospital in Manchester (UK). She was a member of the EMA SAG (Scientific Advisory Group). She is serving as ESMO Council member as the Chair of the National Societies Committee. She was the ESMO National Representative for Italy for 5 years (2011-2017). She is serving on several ESMO Committees (Public Policy extended Committee, Press Committee, Women for Oncology Committee, Lung Cancer faculty, Membership Committee).She used to be an active member of the Young Oncologist Committee. She’s serving on both ESMO, WCLC and ASCO annual congress Lung Cancer Track (2019, and 2020), Chair of ESMO National Societies, from 2019. She is the founder and president of Women for Oncology Italy.

2 million confirmed cases but half of patients are asymptomatic and not tested; pooled prevalance of COVID in cancer patients in Italy was 2%; must take them as high risk patients
they were not prepared for pandemic lasting for months instead of days; March 15 in middle of outbreak they started TERAVOLT registry; by March 26 had IRB approval; they are accruing 17 new patients per week; Ontario also joined in and has become worldwide (21 countries involved); in registry they also included radiologic exams and COVID testing result
most patients were males and many smokers; 75% had SCLC; 83% of cases had one comorbility like hypertension and one third had at least one comorbility; 73.9% of patients were on treatment (they see this in their clinic: 30% on chemo or TKI alone; other patients were just on folowup
most of symptoms overlap with symptoms of lung cancer like pneumonia and pneumonitits and multi organ failure; most were hospitalized
unexpected high mortality among lung cancer patients with COVID19; this mortality seems due to COVID and not to cancer;
study had some limitations like short followup and some surgical cases so some bias may be present
she stresses don’t go it alone and make your own registry JOIN A REGISTRY

Outcome of cancer patients infected with COVID-19, including toxicity of cancer treatments
Fabrice Barlesi @barlesi
Gustave Roussy Cancer Campus

Professor Fabrice Barlesi

As a specialist in lung cancer, precision medicine and cancer immunology, Prof. Fabrice Barlesi is a major contributor to research in the field of novel oncological therapies. He was apppointed General Director of Gustave Roussy in January 2020.

Fabrice Barlesi is Professor of Medicine at the University of Aix-Marseille. He has been head of the Multidisciplinary Oncology and Innovative Therapies Department of the Nord Hospital in Marseille (Marseille Public Hospitals) and the Marseille Centre for Early Trials in Oncology (CLIP2) which were established by him. He holds a doctorate in Sciences and Management with methods of analysis of health care systems, together with an ESSEC (international business school) master’s degree in general hospital management.

Professor Barlesi was also a co-founder of the Marseille Immunopôle French Immunology network, which aims to coordinate immunological expertise in the Aix-Marseille metropolitan area. In this context, he has organised PIONeeR (Investment in the future RHU 2017), the major international Hospital-University research project whose objective is to improve understanding of resistance to immunotherapy – anti-PD1(L1) – in lung cancer and help to prevent and overcome it. He was also vice-chair of the PACA (Provence, Alps and Côte d’Azur) Region Cancer Research Directorate.

Professor Barlesi is the author and co-author of some 300 articles in international journals and specialist publications. In 2018, the European Society of Medical Oncology (ESMO) and the International Association for the Study of Lung Cancer (IASLC) awarded him the prestigious Heine H. Hansen prize. He appears in the 2019 world list of most influential researchers (Highly cited researchers, Web of Science Group).

March 14 started protective measures and at peak had increased commited beds at highest rate
12% of cancer patients tested positive for COVID; (by RTPCR); they curated data across different chemo regimens used
they retrospectively collected data; primary endpoint was clinical worsening; median of disease 13 days;
they actually had more breast cancer patients and other solid malignancies; 23% of covid cases no symptoms; 83% finally did have the symptoms after followup; diarhea actually in 10% of cases so clinics are seeing this as a symptom
CT scan showed 66% cases had pneumonitits like display; 25% patients were managed as outpatient
24% patients worsened during treatment but 75% were able to go home (treated at home or well)
I/O did not have negative outcome and you can use these drugs without increasing risk to COVID
although many clinical trials have been hindered they are actively recruiting for COVID-cancer studies
outcomes with respect to death and symptoms are comparable to worldwide stats

Adapting oncologic practice to COVID19 outbreak: From outpatient triage to risk assessment for specific treatment in Madrid, Spain
Carlos Gomez-Martin
Octubre University Hospital

MOST slides were DO NOT POST so as requested data will not be shown; this study will be published soon
Summary is that Spain is seeing statistics like other European countries and similar results
Tocilizumab, the IL6 antagonists had been suggested as a treatment for cytokine storm and they are involved in a trial with this agent; results will be published

Experience in using oncology drugs in patients with COVID-19

Paolo A. Ascierto
Istituto Nazionale Tumori IRCCS Fondazione Pascale

giving surgery only for patients at highest risk of cancer mortality so using neoadjuvant therapy more often
telemedicine is a viable strategy for patient consult
for metastatic melanoma they are given highest priority for treatment
they are conducting a tocilizumab clinical trial and have accrued over 300 patients
results are in press so please look for publication soon
also can use TNF inhibitor, JAK inhibitor, IL1 inhibitor to treat cytokine storm

COVID-19 and cancer: Flattening the curve but widening disparities
Louis P. Voigt
Memorial Sloan Kettering Cancer Center

Sloan has performed about 5000 COVID tests; 78 patients needed hospitilization; 15 died; 40% still in ICU
they do see many African American patients
mortality rates in US (published) have been around 50-60 % for cancer patients with COVID; Sloan prelim results are lower but still accruing data

Patients with cancer appear more vulnerable to SARS-COV-2: A multi-center study during the COVID-19 outbreak
Hongbing Cai
Zhongnan Hospital of Wuhan University

metastatic cancer showed much higher risk than non cancer but non metastatic showed increased risk too
main criteria of outcome was ICU admission
patients need to be isolated and personalized treatment plans need to be made
many comparisons were between non cancer and cancer which was clearest significance; had not looked at cancer types or stage grade or treatment
it appears that there are more questions right now than answers so data collection is a priority

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For other Articles on the Online Open Access Journal on COVID19 and Cancer please see

https://pharmaceuticalintelligence.com/coronavirus-portal/

Opinion Articles from the Lancet: COVID-19 and Cancer Care in China and Africa

Actemra, immunosuppressive which was designed to treat rheumatoid arthritis but also approved in 2017 to treat cytokine storms in cancer patients SAVED the sickest of all COVID-19 patients

The Second in a Series of Virtual Town Halls with Leading Oncologist on Cancer Patient Care during COVID-19 Pandemic: What you need to know

Responses to the COVID-19 outbreak from Oncologists, Cancer Societies and the NCI: Important information for cancer patients

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Symposium New Drugs on the Horizon Part 1 4:50- 6:00 pm

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Conference Coverage with Social Media, interventional oncology, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, tagged AACR, American Association for Cancer Research, Cancer Drug Discovery on April 27, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Symposium New Drugs on the Horizon Part 1 4:50- 6:00 pm

Reporter: Stephen J. Williams, PhD.

SESSION VSY.DDT01 – New Drugs on the Horizon: Part 1

April 27, 2020, 4:50 PM – 6:05 PM
Virtual Meeting: All Session Times Are U.S. EDT

Session Type
Virtual Symposium
Track(s)
Experimental and Molecular Therapeutics,Drug Development
10 Presentations
4:50 PM – 6:00 PM
– CochairAndrew J. Phillips. C4 Therapeutics, Watertown, MA

4:50 PM – 6:00 PM
– CochairMichael Brands. Bayer Pharma AG, Berlin, Germany

4:50 PM – 4:54 PM
– IntroductionAndrew J. Phillips. C4 Therapeutics, Watertown, MA

4:54 PM – 5:14 PM
DDT01-01 – A first-in-class Menin-MLL1 antagonist for the treatment of MLL-r and NPM1 mutant leukemias Jerry McGeehan. Syndax Pharmaceuticals, Inc., Waltham, MA

Their inhibitor binds to C terminus of Menin MLL1 which is required for AML progression
MLL-4 is from a translocation causing a fusion protein; the inhibitor block leukemic transcription program
anti transcription program when Menin inhibitor is used; displaces Menin from chromatin

worked in tumor models
their inhibitors have good antiproliferative activity seems has good bio-availability in rat and dog
they have active QT signal (cardiac tox) screen program in their clinical studies
initial pre phase1 have not found the max effective dose
not a complete response so may have to look at combination

5:14 PM – 5:17 PM
– Discussion

5:17 PM – 5:37 PM
DDT01-02 – BAY 2416964: The first Aryl Hydrocarbon Receptor (AhR) inhibitor to enter phase I clinical development as a novel cancer immunotherapy. Ilona Gutcher, Christina Kober, Julian Röwe, Ulrike Roehn, Lars Roese, Florian Prinz, Detlef Stoeckigt, Benjamin Bader, Matyas Gorjanacz, Rafael Carretero, Norbert Schmees, Horst Irlbacher, Helge Roider, Katharina Sahm, Hilmar Weinmann, Ingo V. Hartung, Bertolt Kreft, Rienk Offringa, Michael Platten. Bayer AG, Berlin, Germany, Bayer AG, Germany, DKFZ, Heidelberg, Germany

has a more proinflammatory effect in vivo than other I/O inhibitors
rescues TNF alpha immunomodulation
further increases IL2 and IFN gamma when combined with I/O inhibitor so by a different mechanism
looking to use in NSCLC
prelim tox looks fine

5:37 PM – 5:40 PM
– Discussion

5:40 PM – 6:00 PM
DDT01-03 – IPN60090: A potent and selective inhibitor of glutaminase being developed for KEAP1/NFE2L2 mutant NSCLC and ASNS-low HGSOC patients. Jeffrey J. Kovacs. UT MD Anderson Cancer Center, Houston, TX

@MDAndersonNews

Being developed for NSCLC and high grade serous ovarian cancer
glutaminolysis repsonsible for many of the building blocks of cell function
these compounds had selective antiproliferative but was focus on GLS1
good PK and bioavailability; mouse half life is short but dog is longer so estimated human is 8 hours
increased pentose phosphate pathway; reliance on GLS1 activity promotes metabolic reprogramming
the inhibitor significantly reduced glutathione in responder cell lines; responders had higher level of ROS
use ribose pathway and pentose shunt to help deal with REDOX
get a antitumor response in KEAP mut PDX models and these PDX respond poorly to I/O checkpoint inhibitors
ASN2 was higher in nonresponders (alt. formation of Gln) as well as GPT2
ASN2 high expressing nonresponding OVCA lines; need low ASN2 in OVCA for response
so given metabolic plasticity used shRNA screens after inhibitor
PI3K turned up so can use mTORC inhibitor in combo; works well with GLS1 inhibitor to inhibit tumorigenesis
they are looking at other combos including std. chemo and I/O checkpoints
currently doing dose escalation clinical study

6:00 PM – 6:04 PM
– Discussion

6:04 PM – 6:05 PM
– Closing Remarks Michael Brands. Bayer Pharma AG, Berlin, Germany

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Drugging Undrugged Cancer Targets 1:30 pm – 5:00 pm

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Conference Coverage with Social Media, Immunotherapy, Modulating Macrophages in Cancer Immunotherapy, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, tumor microenvironment, tagged #endcancer, AACR, American Association for Cancer Research, cancer conference, cancer immunotherapeutics, coupled with MTOR, immune checkpoint, MEK inhibition, mTOR, real time conference coverage, Resistance to MEK inhibitors on April 27, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Drugging Undrugged Cancer Targets 1:30 pm – 5:00 pm

SESSION VMS.ET01.01 – Drugging Undrugged Cancer Targets

April 27, 2020, 1:30 PM – 3:30 PM
Virtual Meeting: All Session Times Are U.S. EDT

Session Type
Virtual Minisymposium
Track(s)
Experimental and Molecular Therapeutics,Drug Development
18 Presentations
1:30 PM – 1:30 PM
– ChairpersonPeter C. Lucas. University of Pittsburgh School of Medicine, Pittsburgh, PA

1:30 PM – 1:30 PM
– ChairpersonJohn S. Lazo. University of Virginia, Charlottesville, VA

1:30 PM – 1:35 PM
– IntroductionPeter C. Lucas. University of Pittsburgh School of Medicine, Pittsburgh, PA

1:35 PM – 1:45 PM
3398 – PTPN22 is a systemic target for augmenting antitumor immunityWon Jin Ho, Jianping Lin, Ludmila Danilova, Zaw Phyo, Soren Charmsaz, Aditya Mohan, Todd Armstrong, Ben H. Park, Elana J. Fertig, Zhong-Yin Zhang, Elizabeth M. Jaffee. Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD, Purdue University, Baltimore, MD, Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD, Vanderbilt University Medical Center, Baltimore, MD

Abstract: Remarkable progress in cancer immunology has revolutionized cancer therapy. The majority of patients, however, do not respond to immunotherapeutic options, warranting the ongoing search for better strategies. Leveraging the established role of protein tyrosine phosphatase non-receptor type 22 (PTPN22) in autoimmune diseases, we hypothesized that PTPN22 is a novel target for cancer immunotherapy. PTPN22 is a physiologic regulator of T cell receptor (TCR) signaling acting by dephosphorylating activating tyrosine residues in Lck and Zap70. We first confirmed the relevance of PTPN22 expression by exploring its expression in multiple human cancer types using The Cancer Genome Atlas (TCGA). PTPN22 expression positively correlated with T cell and M1 macrophage gene signatures and immune regulatory genes, especially inflamed tumor types. Next, we directly investigated the role of PTPN22 in antitumor immunity by comparing in vivo tumor characteristics in wild-type (WT) and PTPN22 knockout (KO) mice. Consistent with our hypothesis, PTPN22 KO mice resisted MC38 and EG7 tumors significantly compared with WT. Mass cytometry (CyTOF) profiling of the immune tumor microenvironment demonstrated that MC38 tumors in PTPN22 KO mice were infiltrated with greater numbers of T cells, particularly CD8+ T cells expressing granzyme B and PD1. To further delineate the effects of PTPN22 KO on TCR signaling, we established an optimized CyTOF panel of 9 phosphorylation sites involved in the TCR signaling pathway, including two enzymatic substrates of PTPN22 (Lck Y394 and Zap70 Y493) and 15 immune subtyping markers. CyTOF phospho-profiling of CD8 T cells from tumor-bearing mouse spleens and the peripheral blood of immunotherapy-naïve cancer patients showed that the phosphorylated state of Zap70 Y493 correlated strongly with granzyme B expression. Furthermore, phospho-profiling of tumor-infiltrating CD8+ T cells (a measure of T cell activation) revealed the highest TCR-pathway phosphorylation levels in memory CD8+ T cells that express PD1. The difference in phosphorylation levels between WT and PTPN22 KO was most pronounced for Lck Y394. Based on these findings, we then hypothesized that PD1 inhibition will further enhance the antitumor immune responses promoted by the lack of PTPN22. Indeed, PTPN22 KO mice bearing MC38 and EG7 tumors responded more significantly to anti-PD1 therapy when compared with tumor-bearing WT mice. Finally, we treated WT tumor bearing mice with two different small molecule inhibitors of PTPN22, one previously published compound, LTV1, and one novel compound, L1 (discovered through structure based synthesis). While both inhibitors phenocopied the PTPN22 KO mice in resisting MC38 tumor growth, L1 treatment gave an immune profile that resembled what was observed in tumor-bearing PTPN22 KO mice. Taken together, our results demonstrate that PTPN22 is a novel systemic target for augmenting antitumor immunity.

can they leverage autoimmune data to look at new targets for checkpoint inhibition; we have a long way to go in immunooncology as only less than 30-40% of cancer types respond
using Cancer Genome Atlas PTPN22 is associated with autoimmune disorders
PTPN22 KO increases many immune cells; macrophages t-cells and when KO in tumors get more t cell infiltrate
PTP KO enhances t cell response, and may be driving t cells to exhaustion
made a inhibitor or PTPN22; antitumor phenotype when given inhibitor was like KO mice; a PDL1 inhibitor worked in KO mice
PTPN22 only in select hematopoetic cells

1:45 PM – 1:50 PM
– Discussion

1:50 PM – 2:00 PM
3399 – Preclinical evaluation of eFT226, a potent and selective eIF4A inhibitor with anti-tumor activity in FGFR1,2 and HER2 driven cancers. Peggy A. Thompson, Nathan P. Young, Adina Gerson-Gurwitz, Boreth Eam, Vikas Goel, Craig R. Stumpf, Joan Chen, Gregory S. Parker, Sarah Fish, Maria Barrera, Eric Sung, Jocelyn Staunton, Gary G. Chiang, Kevin R. Webster. eFFECTOR Therapeutics, San Diego, CA @RuggeroDavide

Abstract: Mutations or amplifications affecting receptor tyrosine kinases (RTKs) activate the RAS/MAPK and PI3K/AKT signaling pathways thereby promoting cancer cell proliferation and survival. Oncoprotein expression is tightly controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex consisting of eIF4A, eIF4E, and eIF4G. eIF4A functions to catalyze the unwinding of secondary structure in the 5’-untranslated region (5’-UTR) of mRNA facilitating ribosome scanning and translation initiation. The activation of oncogenic signaling pathways, including RAS and PI3K, facilitate formation of eIF4F and enhance eIF4A activity promoting the translation of oncogenes with highly structured 5’-UTRs that are required for tumor cell proliferation, survival and metastasis. eFT226 is a selective eIF4A inhibitor that converts eIF4A into a sequence specific translational repressor by increasing the affinity between eIF4A and 5’-UTR polypurine motifs leading to selective downregulation of mRNA translation. The polypurine element is highly enriched in the 5’-UTR of eFT226 target genes, many of which are known oncogenic drivers, including FGFR1,2 and HER2, enabling eFT226 to selectively inhibit dysregulated oncogene expression. Formation of a ternary complex [eIF4A-eFT226-mRNA] blocks ribosome scanning along the 5’-UTR leading to dose dependent inhibition of RTK protein expression. The 5’-UTR sequence dependency of eFT226 translational inhibition was evaluated in cell-based reporter assays demonstrating 10-45-fold greater sensitivity for reporter constructs containing an RTK 5’-UTR compared to a control. In solid tumor cell lines driven by alterations in FGFR1, FGFR2 or HER2, downregulation of RTK expression by eFT226 resulted in decreased MAPK and AKT signaling, potent inhibition of cell proliferation and an induction of apoptosis suggesting that eFT226 could be effective in treating tumor types dependent on these oncogenic drivers. Solid tumor xenograft models harboring FGFR1,2 or HER2 amplifications treated with eFT226 resulted in significant in vivo tumor growth inhibition and regression at well tolerated doses in breast, non-small cell lung and colorectal cancer models. Treatment with eFT226 also decreased RTK protein levels supporting the potential to use these eFT226 target genes as pharmacodynamic markers of target engagement. Further evaluation of predictive markers of sensitivity or resistance showed that RTK tumor models with mTOR mediated activation of eIF4A are most sensitive to eFT226. The association of eFT226 activity in RTK tumor models with mTOR pathway activation provides a means to further enrich for sensitive patient subsets during clinical development. Clinical trials with eFT226 in patients with solid tumor malignancies have initiated.

ternary complex formed blocks transcription selectively downregulating RTKs
drug binds in 5′ UTR and inhibits translation
RTKs activate eIF4 and are also transcribed through them so inhibition destroys this loop; also with KRAS too
main antitumor activity are by an apoptotic mechanisms; refractory tumors are not sensitive to drug induced apoptosis
drug inhibits FGFR2 in colorectal cancer
drug also effective in HER2+ tumors
mTOR mediated eIF4 inhibited by drug
they get prolonged antitumor activity after washout of drug because forms this tight terniary complex

2:00 PM – 2:05 PM
– Discussion

2:05 PM – 2:15 PM
3400 – Adenosine receptor antagonists exhibit potent and selective off-target killing of FOXA1-high cancers: Steven M. Corsello, Ryan D. Spangler, Ranad Humeidi, Caitlin N. Harrington, Rohith T. Nagari, Ritu Singh, Vickie Wang, Mustafa Kocak, Jordan Rossen, Amael Madec, Nancy Dumont, Todd R. Golub. Dana-Farber Cancer Institute, Boston, MA, Broad Institute of MIT and Harvard, Cambridge, MA @corsellos

Abstract: Drugs targeting adenosine receptors were originally developed for the treatment of Parkinson’s disease and are now being tested in immuno-oncology clinical trials in combination with checkpoint inhibitors. We recently reported the killing activity of 4,518 drugs against 578 diverse cancer cell lines determined using the PRISM molecular barcoding approach. Surprisingly, three established adenosine receptor antagonists (CGS-15943, MRS-1220, and SCH-58261) showed potent and selective killing of FOXA1-high cancer cell lines without the need for immune cells. FOXA1 is a lineage-restricted transcription factor in luminal breast cancer, hepatocellular carcinoma, and prostate cancer without known small molecule inhibitors. We find that cytotoxic activity is limited to adenosine antagonists with a three-member aromatic core bound to a furan group, thus indicating a potential off-target mechanism of action. To identify genomic modulators of drug response, we performed genome-wide CRISPR/Cas9 knockout modifier screens. Killing by CGS-15943 and MRS-1220 was rescued by knockout of the aryl hydrocarbon receptor (AHR) and its nuclear partner ARNT. In confirmatory studies, knockout of AHR completely rescued killing by CGS-15943 in multiple cell types. Co-treatment with an AHR small molecule antagonist also rescued cell viability. Knockout of adenosine receptors did not alter drug response. Given that AHR is a known transcriptional regulator, we performed global mRNA sequencing to assess transcriptional changes induced by CGS-15943. The top two genes induced were the p450 enzymes CYP1A1 and CYP1B1. To determine sufficiency, we overexpressed CYP1A1 in a resistant cell line. Ectopic CYP1A1 expression sensitized to CGS-15943-mediated killing. Mass spectrometry revealed covalent trapping of a reactive metabolite by glutathione and potassium cyanide following in vitro incubation with liver microsomes. In addition, treatment of breast cancer cells with CGS-15943 for 24 hours resulted in increased γ-H2AX phosphorylation by western blot, indicative of DNA double stranded breaks. In summary, we identified off-target anti-cancer activity of multiple established adenosine receptor antagonists mediated by activation of AHR. Future studies will evaluate the functional contribution of FOXA1 and activity in vivo. Starting from a phenotypic screening hit, we leverage functional genomics to unlock the underlying mechanism of action. This project will pave the way for developing more effective therapies for biomarker-selected cancers, with potential to improve the care of patients with liver, breast, and prostate cancer.

developed a chemical library of over 6000 compounds (QC’d) to determine drugs that have antitumor effects
used a PRISM barcoded library to make cell lines to screen genotype-phenotype screens
for nononcology drugs fourteen drugs had activity in the PRISM assay
FOXA1 transcription factor high cancer cells seemed to be inhibited best with adenosine receptor inhibitor found in PRISM assay

2:15 PM – 2:20 PM
– Discussion

2:20 PM – 2:30 PM
3401 – Targeting lysosomal homeostasis in ovarian cancer through drug repurposing: Stefano Marastoni, Aleksandra Pesic, Sree Narayanan Nair, Zhu Juan Li, Ali Madani, Benjamin Haibe-Kains, Bradly G. Wouters, Anthony Joshua. University Health Network, Toronto, ON, Canada, Janssen Inc, Toronto, ON, Canada, The Kinghorn Cancer Centre, Sydney, Australia

Background: Drug repurposing has become increasingly attractive as it avoids the long processes and costs associated with drug discovery. Itraconazole (Itra) is a broad-spectrum anti-fungal agent which has an established broad spectrum of activity in human cell lines including cholesterol antagonism and inhibition of Hedgehog and mTOR pathways. Many in vitro, in vivo and clinical studies have suggested anti-proliferative activity both alone and in combination with other chemotherapeutic agents, in particular in ovarian cancer. This study is aimed at supporting the therapeutic potential of Itra and discovering and repurposing new drugs that can increase Itra anticancer activity as well as identifying new targets in the treatment of ovarian cancer.
Methods: We tested a panel of 32 ovarian cancer cell lines with different doses of Itra and identified a subset of cells which showed significant sensitivity to the drug. To identify genetic vulnerabilities and find new therapeutic targets to combine with Itra, we performed a whole genome sensitivity CRISPR screen in 2 cell lines (TOV1946 and OVCAR5) treated with non-toxic (IC10) concentrations of Itra.
Results: Pathway analysis on the top hits from both the screens showed a significant involvement of lysosomal compartments, and in particular dynamics between trans Golgi network and late endosomes/lysosomes, pathways that are affected by the autophagy inhibitor Chloroquine (CQ). We subsequently demonstrated that the combination of Itra and CQ had a synergistic effect in many ovarian cancer cell lines, even in those resistant to Itra. Further, genetic and pharmacological manipulation of autophagy indicated that upstream inhibition of autophagy is not a key mediator of the Itra/CQ mechanism of action. However, combination of Itra with other lysosomotropic agents (Concanamycin A, Bafilomycin A and Tamoxifen) displayed overlapping activity with Itra/CQ, supporting the lysosomal involvement in sensitizing cells to Itra resulted from the CRISPR screens. Analysis of lysosomal pattern and function showed a combined effect of Itra and CQ in targeting lysosomes and neutralizing their activity.
Conclusion: We identified two FDA approved drugs – CQ and Tamoxifen – that can be used in combination with Itra and exert a potent anti-tumor effect in ovarian cancer by affecting lyosomal function and suggesting a likely dependency of these cells on lysosomal biology. Further studies are in progress.

repurposing itraconozole in ovarian cancer potential mechanism of action is pleitropic
increasing doses of chloroquine caused OVCA cell death by accumulating in Golgi

2:30 PM – 2:35 PM
– Discussion

2:35 PM – 2:45 PM
3402 – BCAT1 as a druggable target in immuno-oncologyAdonia E. Papathanassiu, Francesca Lodi, Hagar Elkafrawy, Michelangelo Certo, Hong Vu, Jeong Hun Ko, Jacques Behmoaras, Claudio Mauro, Diether Lambrechts. Ergon Pharmaceuticals, Washington, DC, VIB Cancer Centre-KULeuven, Leuven, Belgium, Alexandria University, Alexandria, Egypt, University of Birmingham, Birmingham, United Kingdom, Ergon Pharmaceuticals, Washington, DC, Imperial College London, London, United Kingdom

2:45 PM – 2:50 PM
– Discussion

2:50 PM – 3:00 PM
3403 – Drugging the undruggable: Lessons learned from protein phosphatase 2A: Derek Taylor, Goutham Narla. Case Western Reserve University, Cleveland, OH, University of Michigan, Ann Arbor, MI @gouthamnarla

Abstract: Protein phosphatase 2A (PP2A) is a key tumor suppressor responsible for the dephosphorylation of many oncogenic signaling pathways. The PP2A holoenzyme is comprised of a scaffolding subunit (A), which serves as the structural platform for the catalytic subunit (C) and for an array of regulatory subunits (B) to assemble. Impairment of PP2A is essential for the pathogenesis of many diseases including cancer. In cancer, PP2A is inactivated through a variety of mechanisms including somatic mutation of the Aαsubunit. Our studies show that the most recurrent Aαmutation, P179R, results in an altered protein conformation which prevents the catalytic subunit from binding. Additionally, correcting this mutation, by expressing wild type PP2A Aαin cell lines harboring the P179R mutation, causes a reduction in tumor growth and metastasis. Given its central role in human disease pathogenesis, many strategies have been developed to therapeutically target PP2A.Our lab developed a series of small molecules activators of protein phosphatase 2A. One of our more advanced analogs in this series, DT-061, drives dephosphorylation and degradation of select pathogenic substrates of PP2A such as c-MYC in cellular and in vivo systems. Additionally, we have demonstrated the phosphomimetics of MYC that prevent PP2A mediated dephosphorylation and degradation markedly reduce the anti-tumorigenic activity of this series of PP2A activators further validating the target-substrate specificity of this approach. Specific mutations in the site of drug interaction or overexpression of the DNA tumor virus small T antigen which has been shown to specifically bind to and inactivate PP2A abrogate the in vivo activity of this small molecule series further validating the PP2A specificity of this approach. Importantly, treatment with DT-061 results in tumor growth inhibition in an array of in vivocancer models and marked regressions in combination with MEKi and PARPi.To further define the mechanism of action of this small molecule series, we have used cryo-electron microscopy (cryo-EM) to visualize directly theinteraction between DT-061 and a PP2A heterotrimeric complex. We have identified molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme through the marked prolongation of the kOFF of the native complex. Furthermore, we demonstrate that DT-061 specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate oncogenic targets such as c-MYC in both cellular and in vivo systems. This 3.6 Å structure identifies dynamic molecular interactions between the three distinct PP2A subunits and highlight the inherent mechanisms of PP2A complex assembly and disassembly in both cell free and cellular systems. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for the therapeutic targeting of previously undruggable proteins, and aid in the development of phosphatase-based therapeutics tailored against disease specific phosphor-protein targets. The marriage of multidisciplinary scientific practices has allowed us to present here a previously unrecognized therapeutic strategy of complex stabilization for the activation of endogenous disease combating enzymes.

Reactivating PP2A; dephosphorylation of proteins (serine/threonine phosphatases); regulates multiple processes in the cell
SV40T has an antigen that inactivates PP2A; recurrent mutations in high grade endometrial cancers
P179R mutation promotes uterine tumor formation (also in a distal tubule ligation model)
project started in a phenotypic screen that tricyclic antidepressants could have an off target which was phosphatase activators (uncoupling GPCR from anticancer activity)
small T antigen block the activity of these small molecule activators;
acts as a molecular glue to bring the activators with a heterotrimer of phosphatases
so their small molecule activators effective in triple negative breast cancers; one of targets of PP2A is MYC
question: have not yet seen resistance to these compounds but are currently looking at this

3:00 PM – 3:05 PM
– Discussion

3:05 PM – 3:15 PM
3404 – Inhibition of BCL10-MALT1 interaction to treat diffuse large B-cell lymphomaH: eejae Kang, Dong Hu, Marcelo Murai, Ahmed Mady, Bill Chen, Zaneta Nikolovska-Coleska, Linda M. McAllister-Lucas, Peter C. Lucas. University of Pittsburgh School of Medicine, Pittsburgh, PA, Merck, Kenilworth, NJ, University of Michigan School of Medicine, Ann Arbor, MI, University of Pittsburgh School of Medicine, Pittsburgh, PA, University of Michigan School of Medicine, Ann Arbor, MI, UPMC Children’s Hospital, Pittsburgh, PA

Abstract: The CARMA1/BCL10/MALT1 (CBM) signaling complex mediates antigen receptor-induced activation of NF-kB in lymphocytes to support normal adaptive immunity. As the effector protein of the complex, MALT1 exhibits two activities: protease and scaffolding activities. Gain-of-function mutations in the CARMA1 moiety or its upstream regulators trigger antigen-independent assembly of oligomeric CBM complexes, leading to constitutive activation of MALT1, unregulated NF-kB activity, and development of Activated B-Cell subtype of Diffuse Large B-Cell Lymphoma (ABC-DLBCL). Existing MALT1 inhibitors block only MALT1 protease activity, causing incomplete and unbalanced inhibition of MALT1, and have the potential for inducing autoimmune side effects. Since MALT1 is recruited to the CBM complex via its interaction with BCL10, we sought to identify inhibitors of BCL10-MALT1 interaction in order to target both the protease and scaffolding activities of MALT1 to treat ABC-DLBCL.
Our previous work suggested that an antibody-epitope-like interface governs the interaction between BCL10 and MALT1, so that a therapeutic opportunity exists for developing a small molecule inhibitor of the interaction to terminate inappropriate CBM activity. Using co-immunoprecipitation studies, a mammalian two-hybrid system, and surface plasmon resonance (SPR), we confirmed that BCL10 residues 107-119 and the tandem Ig-like domains of MALT1 are critical for this interaction. We then performed a structure-guided in silico screen of 3 million compounds, based on a computational model of the BCL10-MALT1 interaction interface, to identify compounds with potential for disrupting the interaction.
Compound 1 from the initial screening hits showed dose-responsive inhibition of BCL10-MALT1 interaction in both SPR and ELISA-based assays. Functionally, Compound 1 inhibits both MALT1 protease and scaffolding activities in Jurkat T cells, as demonstrated by its inhibition of CD3/CD28-induced RelB and N4BP1 cleavage, and inhibition of IKK phosphorylation, respectively. Compound 1 also blocks IL-2 transcription and IL-2 secretion by PMA/ionomycin-treated Jurkat T cells, as well as constitutive CBM-dependent secretion of IL-6 and IL-10 by ABC-DLBCL cells. Accordingly, Compound 1 selectively suppresses the growth of ABC-DLBCL cell lines, but does not affect the growth of MALT1-independent GCB-DLBCL cell lines.
In conclusion, we have identified an early-stage small molecule compound that inhibits the BCL10-MALT1 interaction, MALT1 protease and scaffolding activities, downstream CBM-dependent signaling, and ABC-DLBCL cell growth. Structure-guided modification of this lead compound is underway to further develop a new class of protein-protein interaction inhibitors that could provide more efficacious blockade of MALT1, while offering protection from undesirable autoimmune side effects in the treatment of this aggressive form of lymphoma.

3:15 PM – 3:20 PM
– Discussion

3:20 PM – 3:30 PM
– Closing RemarksJohn S. Lazo. University of Virginia, Charlottesville, VA

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Signaling in Cancer 11:45am-1:30 pm

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cancer Screening, Cell Biology, Cell Biology, Signaling & Cell Circuits, Conference Coverage with Social Media, Curation, Open Access Journals, Precision Cancer Medicine, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, Scientific & Biotech Conferences: Press Coverage, Scientific Publishing, Signaling, tagged AACR, American Association for Cancer Research, cancer conference, Cancer research, Conference Coverage with Social Media, real time conference coverage, Twitter on April 27, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Signaling in Cancer 11:45am-1:30 pm

Reporter: Stephen J. Williams, PhD.

SESSION VMS.MCB01.01 – Emerging Signaling Vulnerabilities in Cancer
April 27, 2020, 11:45 AM – 1:30 PM
Virtual Meeting: All Session Times Are U.S. EDT
DESCRIPTION

All session times are U.S. Eastern Daylight Time (EDT). Access to AACR Virtual Annual Meeting I sessions are free with registration. Register now at http://www.aacr.org/virtualam2020

Session Type

Virtual Minisymposium

Track(s)

Molecular and Cellular Biology/Genetics

16 Presentations
11:45 AM – 1:30 PM
– Chairperson

J. Silvio Gutkind. UCSD Moores Cancer Center, La Jolla, CA

11:45 AM – 1:30 PM
– Chairperson

in 80’s and 90’s signaling focused on defects and also oncogene addiction. Now the field is switching to finding vulnerabilities in signaling cascades in cancer

Adrienne D. Cox. University of North Carolina at Chapel Hill, Chapel Hill, NC

11:45 AM – 11:55 AM
– Introduction

J. Silvio Gutkind. UCSD Moores Cancer Center, La Jolla, CA

11:55 AM – 12:05 PM
1085 – Interrogating the RAS interactome identifies EFR3A as a novel enhancer of RAS oncogenesis

Hema Adhikari, Walaa Kattan, John F. Hancock, Christopher M. Counter. Duke University, Durham, NC, University of Texas MD Anderson Cancer Center, Houston, TX

Abstract: Activating mutations in one of the three RAS genes (HRAS, NRAS, and KRAS) are detected in as much as a third of all human cancers. As oncogenic RAS mediates it tumorigenic signaling through protein-protein interactions primarily at the plasma membrane, we sought to document the protein networks engaged by each RAS isoform to identify new vulnerabilities for future therapeutic development. To this end, we determined interactomes of oncogenic HRAS, NRAS, and KRAS by BirA-mediated proximity labeling. This analysis identified roughly ** proteins shared among multiple interactomes, as well as a smaller subset unique to a single RAS oncoprotein. To identify those interactome components promoting RAS oncogenesis, we created and screened sgRNA library targeting the interactomes for genes modifying oncogenic HRAS-, NRAS-, or KRAS-mediated transformation. This analysis identified the protein EFR3A as not only a common component of all three RAS interactomes, but when inactivated, uniformly reduced the growth of cells transformed by any of the three RAS isoforms. EFR3A recruits a complex containing the druggable phosphatidylinositol (Ptdlns) 4 kinase alpha (PI4KA) to the plasma membrane to generate the Ptdlns species PI4P. We show that EFR3A sgRNA reduced multiple RAS effector signaling pathways, suggesting that EFR3A acts at the level of the oncoprotein itself. As lipids play a critical role in the membrane localization of RAS, we tested and found that EFR3A sgRNA reduced not only the occupancy of RAS at the plasma membrane, but also the nanoclustering necessary for signaling. Furthermore, the loss of oncogenic RAS signaling induced by EFR3A sgRNA was rescued by targeting PI4K to the plasma membrane. Taken together, these data support a model whereby EFR3A recruits PI4K to oncogenic RAS to promote plasma membrane localization and nonclustering, and in turn, signaling and transformation. To investigate the therapeutic potential of this new RAS enhancer, we show that EFR3A sgRNA reduced oncogenic KRAS signaling and transformed growth in a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines. Encouraged by these results we are exploring whether genetically inactivating the kinase activity of PI4KA inhibits oncogenic signaling and transformation in PDAC cell lines. If true, pharmacologically targeting PI4K may hold promise as a way to enhance the anti-neoplastic activity of drugs targeting oncogenic RAS or its effectors.

@DukeU

@DukeMedSchool

@MDAndersonNews

different isoforms of ras mutations exist differentially in various tumor types e.g. nras vs kras
the C terminal end serve as hotspots of mutations and probably isoform specific functions
they determined the interactomes of nras and kras and determined how many candidates are ras specific
they overlayed results from proteomic and CRSPR screen; EFR3a was a potential target that stuck out
using TCGA patients with higher EFR3a had poorer prognosis
EFR3a promotes Ras signaling; and required for RAS driven tumor growth (in RAS addicted tumors?)
EGFR3a promotes clustering of oncogenic RAS at plasma membrane

12:05 PM – 12:10 PM
– Discussion

12:10 PM – 12:20 PM
1086 – Downstream kinase signaling is dictated by specific KRAS mutations; Konstantin Budagyan, Jonathan Chernoff. Drexel University College of Medicine, Philadelphia, PA, Fox Chase Cancer Center, Philadelphia, PA @FoxChaseCancer

Abstract: Oncogenic KRAS mutations are common in colorectal cancer (CRC), found in ~50% of tumors, and are associated with poor prognosis and resistance to therapy. There is substantial diversity of KRAS alleles observed in CRC. Importantly, emerging clinical and experimental analysis of relatively common KRAS mutations at amino acids G12, G13, A146, and Q61 suggest that each mutation differently influences the clinical properties of a disease and response to therapy. For example, KRAS G12 mutations confer resistance to EGFR-targeted therapy, while G13D mutations do not. Although there is clinical evidence to suggest biological differences between mutant KRAS alleles, it is not yet known what drives these differences and whether they can be exploited for allele-specific therapy. We hypothesized that different KRAS mutants elicit variable alterations in downstream signaling pathways. To investigate this hypothesis, we created a novel system by which we can model KRAS mutants in isogenic mouse colon epithelial cell lines. To generate the cell lines, we developed an assay using fluorescent co-selection for CRISPR-driven genome editing. This assay involves simultaneous introduction of single-guide RNAs (sgRNAs) to two different endogenous loci resulting in double-editing events. We first introduced Cas9 and blue fluorescent protein (BFP) into mouse colon epithelial cell line containing heterozygous KRAS G12D mutation. We then used sgRNAs targeting BFP and the mutant G12D KRAS allele along with homology-directed repair (HDR) templates for a GFP gene and a KRAS mutant allele of our choice. Cells that successfully undergo HDR are GFP-positive and contain the desired KRAS mutation. Therefore, selection for GFP-positive cells allows us to identify those with phenotypically silent KRAS edits. Ultimately, this method allows us to toggle between different mutant alleles while preserving the wild-type allele, all in an isogenic background. Using this method, we have generated cell lines with endogenous heterozygous KRAS mutations commonly seen in CRC (G12D, G12V, G12C, G12R, G13D). In order to elucidate cellular signaling pathway differences between the KRAS mutants, we screened the mutated cell lines using a small-molecule library of ~160 protein kinase inhibitors. We found that there are mutation-specific differences in drug sensitivity profiles. These observations suggest that KRAS mutants drive specific cellular signaling pathways, and that further exploration of these pathways may prove to be valuable for identification of novel therapeutic opportunities in CRC.

Flourescent coselection of KRAS edits by CRSPR screen in a colorectal cancer line; a cell that is competent to undergo HR can undergo combination multiple KRAS
target only mutant allele while leaving wild type intact;
it was KRAS editing event in APC +/- mouse cell line
this enabled a screen for kinase inhibitors that decreased tumor growth in isogenic cell lines; PKC alpha and beta 1 inhibitors, also CDK4 inhibitors inhibited cell growth
questions about heterogeneity in KRAS clones; they looked at off target guides and looked at effects in screens; then they used top two clones that did not have off target; questions about 3D culture- they have not done that; Question ? dependency on AKT activity? perhaps the G12E has different downstream effectors

12:20 PM – 12:25 PM
– Discussion

12:25 PM – 12:35 PM
1087 – NF1 regulates the RAS-related GTPases, RRAS and RRAS2, independent of RAS activity; Jillian M. Silva, Lizzeth Canche, Frank McCormick. University of California, San Francisco, San Francisco, CA @UCSFMedicine

@UCSFCancer\

Abstract: Neurofibromin, which is encoded by the neurofibromatosis type 1 (NF1) gene, is a tumor suppressor that acts as a RAS-GTPase activating protein (RAS-GAP) to stimulate the intrinsic GTPase activity of RAS as well as the closely related RAS subfamily members, RRAS, RRAS2, and MRAS. This results in the conversion of the active GTP-bound form of RAS into the inactive GDP-bound state leading to the downregulation of several RAS downstream effector pathways, most notably MAPK signaling. While the region of NF1 that regulates RAS activity represents only a small fraction of the entire protein, a large extent of the NF1 structural domains and their corresponding mechanistic functions remain uncharacterized despite the fact there is a high frequency of NF1 mutations in several different types of cancer. Thus, we wanted to elucidate the underlying biochemical and signaling functions of NF1 that are unrelated to the regulation of RAS and how loss of these functions contributes to the pathogenesis of cancer. To accomplish this objective, we used CRISPR-Cas9 methods to knockout NF1 in an isogenic “RASless” MEF model system, which is devoid of the major oncogenic RAS isoforms (HRAS, KRAS, and NRAS) and reconstituted with the KRAS4b wild-type or mutant KRAS^G12C or KRAS^G12D isoform. Loss of NF1 led to elevated RAS-GTP levels, however, this increase was not as profound as the levels in KRAS-mutated cells or provided a proliferative advantage. Although ablation of NF1 resulted in sustained activation of MAPK signaling, it also unexpectedly, resulted in a robust increase in AKT phosphorylation compared to KRAS-mutated cells. Surprisingly, loss of NF1 in KRAS4b wild-type and KRAS-mutated cells potently suppressed the RAS-related GTPases, RRAS and RRAS2, with modest effects on MRAS, at both the transcript and protein levels. A Clariom™D transcriptome microarray analysis revealed a significant downregulation in the NF-κB target genes, insulin-like growth factor binding protein 2 (IGFBP2), argininosuccinate synthetase 1 (ASS1), and DUSP1, in both the NF1 knockout KRAS4b wild-type and KRAS-mutated cells. Moreover, NF1^Null melanoma cells also displayed a potent suppression of RRAS and RRAS2 as well as these NF-κB transcription factors. Since RRAS and RRAS2 both contain the same NF-κB transcription factor binding sites, we hypothesize that IGFBP2, ASS1, and/or DUSP1 may contribute to the NF1-mediated regulation of these RAS-related GTPases. More importantly, this study provides the first evidence of at least one novel RAS-independent function of NF1 to regulate the RAS-related subfamily members, RRAS and RRAS2, in a manner exclusive of its RAS-GTPase activity and this may provide insight into new potential biomarkers and molecular targets for treating patients with mutations in NF1.

NF1 and SPRED work together to signal from RTK cKIT through RAS
NF1 knockout cells had higher KRAS and had increased cell proliferation
NF1 -/- or SPRED loss had increased ERK phosphorylation and some increase in AKT activity compared to parental cells
they used isogenic cell lines devoid of all RAS isoforms and then reconstituted with specific RAS WT or mutants
NF1 and SPRED KO both reduce RRAS expression; in an AKT independent mannner
NF1 SPRED KO cells have almost no IGFBP2 protein expression and SNAIL so maybe affecting EMT?
this effect is independent of its RAS GTPAse activity (noncanonical)

12:35 PM – 12:40 PM
– Discussion

12:40 PM – 12:50 PM
1088 – Elucidating the regulation of delayed-early gene targets of sustained MAPK signaling; Kali J. Dale, Martin McMahon. University of Utah, Salt Lake City, UT, Huntsman Cancer Institute, Salt Lake City, UT

@huntsmancancer

Abstract: RAS and its downstream effector, BRAF, are commonly mutated proto-oncogenes in many types of human cancer. Mutationally activated RAS or BRAF signal through the MEK→ERK MAP kinase (MAPK) pathway to regulate key cancer cell hallmarks such as cell division cycle progression, reduced programmed cell death, and enhanced cell motility. Amongst the list of RAS/RAF-regulated genes are those encoding integrins, alpha-beta heterodimeric transmembrane proteins that regulate cell adhesion to the extracellular matrix. Altered integrin expression has been linked to the acquisition of more aggressive behavior by melanoma, lung, and breast cancer cells leading to diminished survival of cancer patients. We have previously documented the ability of the RAS-activated MAPK pathway to induce the expression of ITGB3 encoding integrin β3 in several different cell types. RAS/RAF-mediated induction of ITGB3 mRNA requires sustained, high-level activation of RAF→MEK→ERK signaling mediated by oncogene activation and is classified as “delayed-early”, in that it is sensitive to the protein synthesis inhibitor cycloheximide. However, to date, the regulatory mechanisms that allow for induced ITGB3 downstream of sustained, high-level activation of MAPK signaling remains obscure. We have identified over 300 DEGs, including those expressing additional cell surface proteins, that display similar regulatory characteristics as ITGB3. We use integrin β3 as a model to test our hypothesis that there is a different mechanism of regulation for delayed-early genes (DEG) compared to the canonical regulation of Immediate-Early genes. There are three regions in the chromatin upstream of the ITGB3 that become more accessible during RAF activation. We are relating the chromatin changes seen during RAF activation to active enhancer histone marks. To elucidate the essential genes of this regulation process, we are employing the use of a genome-wide CRISPR knockout screen. The work presented from this abstract will help elucidate the regulatory properties of oncogenic progression in BRAF mutated cancers that could lead to the identification of biomarkers.

12:50 PM – 12:55 PM
– Discussion

12:55 PM – 1:05 PM
1090 – Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis

Radha Mukherjee, Kiran Gireesan Vanaja, Jacob A. Boyer, Juan Qiu, Xiaoping Chen, Elisa De Stanchina, Sarat Chandarlapaty, Andre Levchenko, Neal Rosen. Memorial Sloan Kettering Cancer Center, New York, NY, Yale University, West Haven, CT, Memorial Sloan Kettering Cancer Center, New York, NY, Memorial Sloan Kettering Cancer Center, New York, NY @sloan_kettering

Abstract: The PI3K pathway is a key regulator of metabolism, cell proliferation and migration and some of its components (e.g. PIK3CA and PTEN) are frequently altered in cancer by genetic events that deregulate its output. However, PI3K signaling is not usually the primary driver of these tumors and inhibitors of components of the pathway have only modest antitumor effects. We now show that both physiologic and oncogenic activation of the PI3K signaling by growth factors and an activating hotspot PIK3CA mutation respectively, cause an increase in the expression of the lipid phosphatase PTEN, thus limiting the duration of the signal and the output of the pathway in tumors. Pharmacologic and physiologic inhibition of the pathway by HER2/PI3K/AKT/mTOR inhibitors and nutrient starvation respectively reduce PTEN, thus buffering the effects of inhibition and contributing to the rebound in pathway activity that occurs in tumors. This regulation is found to be a feature of multiple types of cancer, non-cancer cell line and PDX models thereby highlighting its role as a key conserved feedback loop within the PI3K signaling network, both in vitro and in vivo. Regulation of expression is due to mTOR/4EBP1 dependent control of PTEN translation and is lost when 4EBP1 is knocked out. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the output of oncogenic mutants that deregulate the pathway and the antitumor activity of PI3K pathway inhibitors.

mTOR can be a potent regulator of PTEN and therefore a major issue when developing PI3K inhibitors

1:05 PM – 1:10 PM
– Discussion

1:10 PM – 1:20 PM
1091 – BI-3406 and BI 1701963: Potent and selective SOS1::KRAS inhibitors induce regressions in combination with MEK inhibitors or irinotecan

Daniel Gerlach, Michael Gmachl, Juergen Ramharter, Jessica Teh, Szu-Chin Fu, Francesca Trapani, Dirk Kessler, Klaus Rumpel, Dana-Adriana Botesteanu, Peter Ettmayer, Heribert Arnhof, Thomas Gerstberger, Christiane Kofink, Tobias Wunberg, Christopher P. Vellano, Timothy P. Heffernan, Joseph R. Marszalek, Mark Pearson, Darryl B. McConnell, Norbert Kraut, Marco H. Hofmann. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria, The University of Texas MD Anderson Cancer Center, Houston, TX, The University of Texas MD Anderson Cancer Center, Houston, TX, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

there is rational for developing an SOS1 inhibitor (GEF); BI3406 shows better PK and PD as a candidate
most sensitive cell lines to inhibitor carry KRAS mutation; NRAS or BRAF mutations are not sensititve
KRAS mutation defines sensitivity so they created KRAS mut isogenic cell lines
found best to co inhibit SOS and MEK as observed plasticity with only SOS
dual combination in lung NSCLC pancreatic showed enhanced efficacy compared to monotherapy
SOS1 inhibition plus irinotecan enhances DNA double strand breaks; no increased DNA damage in normal stroma but preferentially in tumor cells
these SOS1 had broad activity against KRAS mutant models;
phase 1 started in 2019;

@Boehringer

1:20 PM – 1:25 PM
– Discussion

1:25 PM – 1:30 PM
– Closing Remarks

Adrienne D. Cox. University of North Carolina at Chapel Hill, Chapel Hill, NC

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks and Clinical Session 11:45am-1:15pm Advances in Cancer Drug Discovery

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Conference Coverage with Social Media, Curation, Drug Delivery Platform Technology, Drug Development Process, Drug Discovery Chemistry, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacodynamics and Pharmacokinetics, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, Scientific & Biotech Conferences: Press Coverage, Small Molecules in Development of Therapeutic Drugs, tagged #pharmanews, @Biotech News, AACR, American Association for Cancer Research, Cancer, Estrogen receptor alpha, pharmacokinetic, Pharmacokinetics, real time conference coverage, SHP2, small drug development on April 27, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks and Clinical Session 11:45am-1:15pm Advances in Cancer Drug Discovery

SESSION VMS.CH01.01 – Advances in Cancer Drug Design and Discovery

April 27, 2020, 11:45 AM – 1:15 PM
Virtual Meeting: All Session Times Are U.S. EDT
DESCRIPTIONAll session times are U.S. Eastern Daylight Time (EDT).

Session Type
Virtual Minisymposium
Track(s)
Cancer Chemistry
14 Presentations
11:45 AM – 11:45 AM
– ChairpersonZoran Rankovic. St. Jude Children’s Research Hospital, Memphis, TN

11:45 AM – 11:45 AM
– ChairpersonChristopher G. Nasveschuk. C4 Therapeutics, Watertown, MA

11:45 AM – 11:50 AM
– IntroductionZoran Rankovic. St. Jude Children’s Research Hospital, Memphis, TN

11:50 AM – 12:00 PM
1036 – Discovery of a highly potent, efficacious and orally active small-molecule inhibitor of embryonic ectoderm development (EED)Changwei Wang, Rohan Kalyan Rej, Jianfeng Lu, Mi Wang, Kaitlin P. Harvey, Chao-Yie Yang, Ester Fernandez-Salas, Jeanne Stuckey, Elyse Petrunak, Caroline Foster, Yunlong Zhou, Rubin Zhou, Guozhi Tang, Jianyong Chen, Shaomeng Wang. Rogel Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, MI, Ascentage Pharma Group, Taizhou, Jiangsu, China

12:00 PM – 12:05 PM
– Discussion

12:05 PM – 12:15 PM
1037 – Orally available small molecule CD73 inhibitor reverses immunosuppression through blocking of adenosine productionXiaohui Du, Brian Blank, Brenda Chan, Xi Chen, Yuping Chen, Frank Duong, Lori Friedman, Tom Huang, Melissa R. Junttila, Wayne Kong, Todd Metzger, Jared Moore, Daqing Sun, Jessica Sun, Dena Sutimantanapi, Natalie Yuen, Tatiana Zavorotinskaya. ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA

12:15 PM – 12:20 PM
– Discussion

12:20 PM – 12:30 PM
1038 – A potent and selective PARP14 inhibitor decreases pro-tumor macrophage function and elicits inflammatory responses in tumor explantsLaurie Schenkel, Jennifer Molina, Kerren Swinger, Ryan Abo, Danielle Blackwell, Anne Cheung, William Church, Kristy Kuplast-Barr, Alvin Lu, Elena Minissale, Mario Niepel, Melissa Vasbinder, Tim Wigle, Victoria Richon, Heike Keilhack, Kevin Kuntz. Ribon Therapeutics, Cambridge, MA

12:30 PM – 12:35 PM
– Discussion

12:35 PM – 12:45 PM
1039 – Fragment-based drug discovery to identify small molecule allosteric inhibitors of SHP2. Philip J. Day, Valerio Berdini, Juan Castro, Gianni Chessari, Thomas G. Davies, James E. H. Day, Satoshi Fukaya, Chris Hamlett, Keisha Hearn, Steve Hiscock, Rhian Holvey, Satoru Ito, Yasuo Kodama, Kenichi Matsuo, Yoko Nakatsuru, Nick Palmer, Amanda Price, Tadashi Shimamura, Jeffrey D. St. Denis, Nicola G. Wallis, Glyn Williams, Christopher N. Johnson. Astex Pharmaceuticals, Inc., Cambridge, United Kingdom, Taiho Pharmaceutical Co., Ltd, Tsukuba, Japan

Abstract: The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signalling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Recent advances have shown that genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signalling and inhibits proliferation of RTK-driven cancer cell lines. SHP2 is now understood to act upstream of RAS and plays a role in KRAS-driven cancers, an area of research which is rapidly growing. Considering that RTK deregulation often leads to a wide range of cancers and the newly appreciated role of SHP2 in KRAS-driven cancers, SHP2 inhibitors are therefore a promising therapeutic approach.
SHP2 contains two N-terminal tandem SH2 domains (N-SH2, C-SH2), a catalytic phosphatase domain and a C-terminal tail. SHP2 switches between “open” active and “closed” inactive forms due to autoinhibitory interactions between the N-SH2 domain and the phosphatase domain. Historically, phosphatases were deemed undruggable as there had been no advancements with active site inhibitors. We hypothesised that fragment screening would be highly applicable and amenable to this target to enable alternative means of inhibition through identification of allosteric binding sites. Here we describe the first reported fragment screen against SHP2.
Using our fragment-based Pyramid^TM approach, screening was carried out on two constructs of SHP2; a closed autoinhibited C-terminal truncated form (phosphatase and both SH2 domains), as well as the phosphatase-only domain. A combination of screening methods such as X-ray crystallography and NMR were employed to identify fragment hits at multiple sites on SHP2, including the tunnel-like allosteric site reported by Chen et al, 2016. Initial fragment hits had affinities for SHP2 in the range of 1mM as measured by ITC. Binding of these hits was improved using structure-guided design to generate compounds which inhibit SHP2 phosphatase activity and are promising starting points for further optimization.

anti estrogen receptor therapy: ER degraders is one class
AZ9833 enhances degradation of ER alpha
worked in preclinical mouse model (however very specific)
PK parameters were good for orally available in rodents; also in vitro and in vivo correlation correlated in rats but not in dogs so they were not sure if good to go in humans
they were below Km in rats but already at saturated in dogs, dogs were high clearance
predicted human bioavailability at 40%

12:45 PM – 12:50 PM
– Discussion

12:50 PM – 1:00 PM
1042 – Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833Eric T. Gangl, Roshini Markandu, Pradeep Sharma, Andy Sykes, Petar Pop-Damkov, Pablo Morentin Gutierrez, James S. Scott, Dermot F. McGinnity, Adrian J. Fretland, Teresa Klinowska. AstraZeneca, Waltham, MA

1:00 PM – 1:05 PM
– Discussion

1:05 PM – 1:15 PM
– Closing RemarksChristopher G. Nasveschuk. MA

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks 9 am

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cancer Screening, Conference Coverage with Social Media, interventional oncology, Personalized and Precision Medicine & Genomic Research, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, tagged #endcancer, #pharmanews, @pharma_BI, AACR, American Association for Cancer Research, Cancer, cancer conference, Conference Coverage with Social Media, real time conference coverage on April 27, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks and Clinical Session 9 am

Reporter: Stephen J. Williams, PhD.

9:00 AM Opening Session

9:00 AM – 9:05 AM
– Opening Video

9:05 AM – 9:15 AM
– AACR President: Opening Remarks Elaine R. Mardis. Nationwide Children’s Hospital, Columbus, OH

Dr. Elaine R. Mardis, Has Been Named American Association for Cancer Research President-Elect 2018-2019. She will officially become President-Elect at #AACR18: https://t.co/jdum36WIc5 pic.twitter.com/FuKHRfPHCZ

— AACR (@AACR) March 20, 2018

Dr. Mardis is the Robert E. and Louise F. Dunn Distinguished Professor of Medicine @GenomeInstitute at Washington University of St. Louis School of Medicine.

Opening remarks: Dr. Mardis gave her welcome from her office. She expressed many thanks to healthcare workers and the hard work of scientists and researchers. She also expressed some regret for the many scientists who had wonderful research to present and how hard it was to make the decision to go virtual however she feels there now more than ever still needs a venue to discuss scientific and clinical findings. Some of the initiatives that she has had the opportunity to engage in the areas of groundbreaking discoveries and clinical trials. 606,000 lives will be lost in US this year from cancer. AACR is being vigilant as also an advocacy platform and public policy platform in Congress and Washington. The AACR has been at the front of public policy on electronic cigarettes. Blood Cancer Discovery is their newest journal. They are going to host joint conferences with engineers, mathematicians and physicists to discuss how they can help to transform oncology. Cancer Health Disparity Annual Conference is one of the fastest growing conferences. They will release a report later this year about the scope of the problem and policy steps needed to alleviate these disparities. Lack of racial and ethnic minorities in cancer research had been identified an issue and the AACR is actively working to reduce the disparities within the ranks of cancer researchers. Special thanks to Dr. Margaret Foti for making the AACR the amazing organization it is.

9:15 AM – 9:30 AM- AACR Annual Meeting Program Chair: Review of Program for AACR Virtual Annual Meeting Antoni Ribas. UCLA Medical Center, Los Angeles, CA

Dr. Antoni Ribas, @UCLAJCCC, Elected American Association for Cancer Research President-Elect 2019–2020. https://t.co/4MbTy1jEDN pic.twitter.com/zq40gHjfAb

— AACR (@AACR) March 28, 2019

Antoni Ribas, MD PhD is Professor, Medicine, Surgery, Molecular and Medical Pharmacology; Director, Parker Institute for Cancer Immunotherapy Center at UCLA; Director, UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program aribas@mednet.ucla.edu

The AACR felt it was important to keep the discourse in the cancer research field as the Annual AACR meeting is the major way scientists and clinicians discuss the latest and most pertinent results. A three day virtual meeting June 22-24 will focus more on the translational and basic research while this meeting is more focused on clinical trials. There will be educational programs during the June virtual meeting. The COVID in Cancer part of this virtual meeting was put in specially for this meeting and there will be a special meeting on this in July. They have created an AACR COVID task force. The AACR has just asked Congress and NIH to extend the grants due to the COVID induced shutdown of many labs.

9:30 Open Clinical Plenary Session (there are 17 sessions today but will only cover a few of these)

9:30 AM – 9:31 AM
– Chairperson Nilofer S. Azad. Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD @noza512

9:30 AM – 9:31 AM
– Chairperson Manuel Hidalgo. Weill Cornell Medicine, New York, NY

9:30 AM – 9:35 AM
– Introduction Nilofer S. Azad. Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD

9:35 AM – 9:45 AM
CT011 – Evaluation of durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL Lajos Pusztai, et al

see https://www.abstractsonline.com/pp8/#!/9045/presentation/10593

AbstractBackground: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint risk to evaluate novel agents as neoadjuvant therapy for breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/is ypN0)). DNA repair deficiency in cancer cells can lead to immunogenic neoantigens, activation of the STING pathway, and PARP inhibition can also upregulate PD-L1 expression. Based on these rationales we tested the combination of durvalumab (anti-PDL1), olaparib (PARP inhibitor) and paclitaxel in I-SPY2.
Methods: Women with tumors ≥ 2.5 cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone receptor positive (HR+) patients had to have MammaPrint high molecular profile. Treatment included durvalumab 1500 mg every 4 weeks x 3, olaparib 100 mg twice daily through weeks 1-11 concurrent with paclitaxel 80 mg/m2 weekly x 12 (DOP) followed by doxorubicin/cyclophosphamide (AC) x 4. The control arm was weekly paclitaxel x 12 followed by AC x 4. All patients undergo serial MRI imaging and imaging response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Regimens “graduation with success” when the Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial in the appropriate biomarker groups reaches > 85%.
Results: A total of 73 patients received DOP treatment including 21 HR- tumors (i.e. triple-negative breast cancer, TNBC) and 52 HR+ tumors between May 2018 – June 2019. The control group included 299 patients with HER2- tumors. The DOP arm graduated in June 2019, 13 months after enrollment had started, for all HER2- negative and the HR+/HER2- cohorts with > 0.85% predictive probabilities of success. 72 patient completed surgery and evaluable for pCR, the final predicted probabilities of success in a future phase III trial to demonstrate higher pCR rate with DOP compared to control are 81% for all HER2- cancers (estimated pCR rate 37%), 80% for TNBC (estimated pCR rate 47%) and 74.5% for HR+/HER2- patients (estimated pCR rate 28%). Association between pCR and germline BRCA status and immune gene expression including PDL1 will be presented at the meeting. No unexpected toxicities were seen, but 10 patients (14%) had possibly immune or olaparib related grade 2/3 AEs (3 pneumonitis, 2 adrenal insufficiency, 1 colitis, 1 pancreatitis, 2 elevated LFT, 1 skin toxicity, 2 hypothyroidism, 1 hyperthyroidism, 1 esophagitis).
Conclusion: I-SPY2 demonstrated a significant improvement in pCR with durvalumab and olaparib included with paclitaxel compared to chemotherapy alone in women with stage II/III high-risk, HER2-negative breast cancer, improvement was seen in both the HR+ and TNBC subsets.

This combination of durvalumab and olaparib is safe in triple negative breast cancer
expected synergy between PARP inhibitors and PDL1 inhibitors as olaparib inhibits DNA repair and would increase the mutational burden, which is in lung cancer shown to be a biomarker for efficacy of immune checkpoint inhibitors such as Opdivio
three subsets of breast cancers were studied: her2 negative, triple negative and ER+ tumors
MRI imaging tumor size was used as response
olaparib arm had elevation of liver enzymes and there was a pancreatitis
however paclitaxel was used within the combination as well as a chemo arm but the immuno arm alone may not be better than chemo alone but experimental arm with all combo definitely better than chemo alone
they did not look at BRCA1/2 status, followup talk showed that this is a select group that may see enhanced benefit; PARP inhibitors were seen to be effective only in BRCA1/2 mutant ovarian cancer previously

10:10 AM – 10:20 AM
CT012 – Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial Grant A. McArthur,

for abstract please see https://www.abstractsonline.com/pp8/#!/9045/presentation/10594

AbstractBackground: Approved systemic treatments for advanced melanoma include immune checkpoint inhibitor therapy (CIT) and targeted therapy with BRAF plus MEK inhibitors for BRAFV600E/K mutant melanoma. Response rates with CITs are typically lower than those observed with targeted therapy, but CIT responses are more durable. Preclinical and clinical data suggest a potential for synergy between CIT and BRAF plus MEK inhibitors. We therefore evaluated whether combining CIT with targeted therapy could improve efficacy vs targeted therapy alone. Methods: Treatment-naive patients with unresectable stage IIIc/IV melanoma (AJCC 7th ed), measurable disease by RECIST 1.1, and BRAFV600 mutations in their tumors were randomized to the anti-programmed death-ligand 1 antibody A + C + V or placebo (Pbo) + C + V. A or Pbo were given on days 1 and 15 of each 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. The primary outcome was investigator-assessed progression-free survival (PFS). Results: 514 patients were enrolled (A + C + V = 256; Pbo + C + V = 258) and followed for a median of 18.9 months. Investigator-assessed PFS was significantly prolonged with A + C + V vs Pbo + C + V (15.1 vs 10.6 months, respectively; hazard ratio: 0.78; 95% confidence interval: 0.63-0.97; P=0.025), an effect seen in all prognostic subgroups. While objective response rates were similar in the A + C + V and Pbo + C + V groups, median duration of response was prolonged with A + C + V (21.0 months) vs Pbo + C + V (12.6 months). Overall survival data were not mature at the time of analysis. Common treatment-related adverse events (AEs; >30%) in the A + C + V and Pbo + C + V groups were blood creatinine phosphokinase (CPK) increase (51.3% vs 44.8%), diarrhea (42.2% vs 46.6%), rash (40.9% in both arms), arthralgia (39.1% vs 28.1%), pyrexia (38.7% vs 26.0%), alanine aminotransferase (ALT) increase (33.9% vs 22.8%), and lipase increase (32.2% vs 27.4%). Common treatment-related grade 3/4 AEs (>10%) that occurred in the A + C + V and Pbo + C + V groups were lipase increase (20.4% vs 20.6%), blood CPK increase (20.0% vs 14.9%), ALT increase (13.0% vs 8.9%), and maculopapular rash (12.6% vs 9.6%). The incidence of treatment-related serious AEs was similar between the A + C + V (33.5%) and Pbo + C + V (28.8%) groups. 12.6% of patients in the A + C + V group and 15.7% in the Pbo + C + V group stopped all treatment because of AEs. The safety profile of the A + C + V regimen was generally consistent with the known profiles of the individual components. Conclusion: Combination therapy with A + C + V was tolerable and manageable, produced durable responses, and significantly increased PFS vs Pbo + C + V. Thus, A + C + V represents a viable treatment option for BRAFV600 mutation-positive advanced melanoma. ClinicalTrials.gov ID: NCT02908672

10:25 AM – 10:35 AM
CT013 – SWOG S1320: Improved progression-free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma Alain Algazi,

for abstract and more author information please see https://www.abstractsonline.com/pp8/#!/9045/presentation/10595

AbstractBackground: BRAF and MEK inhibitors yield objective responses in the majority of BRAFV600E/K mutant melanoma patients, but acquired resistance limits response durations. Preclinical data suggests that intermittent dosing of these agents may delay acquired resistance by deselecting tumor cells that grow optimally in the presence of these agents. S1320 is a randomized phase 2 clinical trial designed to determine whether intermittent versus continuous dosing of dabrafenib and trametinib improves progression-free survival (PFS) in patients with advanced BRAFV600E/K melanoma.
Methods: All patients received continuous dabrafenib and trametinib for 8-weeks after which non-progressing patients were randomized to receive either continuous treatment or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. Unscheduled treatment interruptions of both drugs for > 14 days were not permitted. Responses were assessed using RECIST v1.1 at 8-week intervals scheduled to coincide with on-treatment periods for patients on the intermittent dosing arm. Adverse events were assessed using CTCAE v4 monthly. The design assumed exponential PFS with a median of 9.4 months using continuous dosing, 206 eligible patients and 156 PFS events. It had 90% power with a two-sided α = 0.2 to detect a change to a median with an a priori hypothesis that intermittent dosing would improve the median PFS to 14.1 months using a Cox model stratified by the randomization stratification factors.
Results: 242 patients were treated and 206 patients without disease progression after 8 weeks were randomized, 105 to continuous and 101 to intermittent treatment. 70% of patients had not previously received immune checkpoint inhibitors. There were no significant differences between groups in terms of baseline patient characteristics. The median PFS was statistically significantly longer, 9.0 months from randomization, with continuous dosing vs. 5.5 months from randomization with intermittent dosing (p = 0.064). There was no difference in overall survival between groups (median OS = 29.2 months in both arms p = 0.93) at a median follow up of 2 years. 77% of patient treated continuously discontinued treatment due to disease progression vs. 84% treated intermittently (p = 0.34).
Conclusions: Continuous dosing with the BRAF and MEK inhibitors dabrafenib and trametinib yields superior PFS compared with intermittent dosing.

combo of MEK and BRAF inhibitors can attract immune cells like TREGs so PDL1 inhibitor might help improve outcome
PFS was outcome endpoint
LDH was elevated in three patients (why are they seeing liver tox? curious like previous study); are seeing these tox with the PDL1 inhibitors
there was marked survival over placebo group and PFS was statistically with continuous dosing however intermittent dosing shows no improvement

Dr. Wafik el Diery gave a nice insight as follows

On-off dosing of cancer drugs does not help melanoma patients #AACR20 https://t.co/qwwlc8vSdJ

— Wafik S. El-Deiry, MD, PhD, FACP (@weldeiry) April 27, 2020

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Live Conference Coverage of AACR 2020 Annual Virtual Meeting; April 27-28, 2020

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Prevention: Research & Programs, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Childhood cancer, Conference Coverage with Social Media, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, tagged #endcancer, AACR, American Association for Cancer Research, Cancer, cancer conference, Cancer research, Conference Coverage with Social Media, https://twitter.com/#!/pharma_BI, real time conference coverage, Twitter on April 26, 2020| Leave a Comment »

Live Conference Coverage of AACR 2020 Annual Virtual Meeting; April 27-28, 2020

Reporter: Stephen J. Williams, Ph.D.

The American Association for Cancer Research (AACR) will hold its Annual Meeting as a Virtual Online Format. Registration is free and open to all, including non members. Please go to

https://www.aacr.org/meeting/aacr-annual-meeting-2020/aacr-virtual-annual-meeting-i/?utm_source=Salesforce%20Marketing%20Cloud&utm_medium=Email&utm_campaign=&sfmc_s=0031I00000WsBJxQAN

to register for this two day meeting. Another two day session will be held in June 2020 and will focus more on basic cancer research.

Please follow @pharma_BI who will be live Tweeting Real Time Notes from this meeting using the hashtag

#AACR20

And @StephenJWillia2

The following is a brief summary of the schedule. Please register and go to AACR for detailed information on individual sessions.

AACR VIRTUAL ANNUAL MEETING I: SCHEDULE AT A GLANCE

AACR Virtual Annual Meeting I is available free Register Now

VIRTUAL MEETING I: BROWSER REQUIREMENTS AND ACCESSVIRTUAL MEETING I: FAQVIRTUAL MEETING I: MEETING PLANNER (ABSTRACT TITLES)

Presentation titles are available through the online meeting planner. The program also includes six virtual poster sessions consisting of brief slide videos. Poster sessions will not be presented live but will be available for viewing on demand. Poster session topics are as follows:

Phase I Clinical Trials
Phase II Clinical Trials
Phase III Clinical Trials
Phase I Trials in Progress
Phase II Trials in Progress
Phase III Trials in Progress

Schedule updated April 24, 2020

MONDAY, APRIL 27

Channel 1		Channel 2		Channel 3
9:00 a.m.-9:30 a.m. Opening Session _______________________
9:30 a.m.-11:40 a.m. Opening Clinical Plenary _______________________
11:40 a.m.-2:00 p.m. Clinical Plenary: Immunotherapy Clinical Trials 1 _______________________	___	11:45 a.m.-1:30 p.m. Minisymposium: Emerging Signaling Vulnerabilities in Cancer _______________________	___	11:45 a.m.-1:15 p.m. Minisymposium: Advances in Cancer Drug Design and Discovery __________________________
2:00 p.m.-4:50 p.m. Clinical Plenary: Lung Cancer Targeted Therapy _______________________	___	1:55 p.m.-4:15 p.m. Clinical Plenary: Breast Cancer Therapy _______________________	___	1:30 p.m.-3:30 p.m. Minisymposium: Drugging Undrugged Cancer Targets __________________________
4:50 p.m.-6:05 p.m. Symposium: New Drugs on the Horizon 1_______________________	___	4:50 p.m.-5:50 p.m. Minisymposium: Therapeutic Modification of the Tumor Microenvironment or Microbiome _______________________	___	4:00 p.m.-6:00 p.m. Minisymposium: Advancing Cancer Research Through An International Cancer Registry: AACR Project GENIE Use Cases__________________________

All session times are EDT.

TUESDAY, APRIL 28

Channel 1		Channel 2		Channel 3
9:00 a.m.-101:00 a.m. Clinical Plenary: COVID-19 and Cancer __________________________
11:00 a.m.-1:35 p.m. Clinical Plenary: Adoptive Cell Transfer Therapy__________________________	___	10:45 a.m.-12:30 p.m. Symposium: New Drugs on the Horizon 2_________________________	___	10:45 a.m.-12:30 p.m. Minisymposium: Translational Prevention Studies ______________________
	___	12:30 p.m.-1:25 p.m. Symposium: New Drugs on the Horizon 3 _________________________	___	12:30 p.m.-2:15 p.m. Minisymposium: Non-coding RNAs in Cancer ______________________
1:35 p.m.-3:35 p.m. Clinical Plenary: Early Detection and ctDNA__________________________	___	1:30 p.m.-3:50 p.m. Clinical Plenary: Immunotherapy Clinical Trials 2 _________________________	___	2:15 p.m.-3:45 p.m. Minisymposium: Novel Targets and Therapies______________________
3:35 p.m.-5:50 p.m. Minisymposium: Predictive Biomarkers for Immunotherapeutics__________________________	___	3:50 p.m.-5:35 p.m. Minisymposium: Evaluating Cancer Genomics from Normal Tissues through Evolution to Metastatic Disease _________________________	___	4:00 p.m.-4:55 p.m. Clinical Plenary: Targeted Therapy______________________
				5:00 p.m.-5:45 p.m. Symposium: NCI Activities– COVID-19 and Cancer Research Dinah Singer, NCI ______________________
				5:45 p.m.-6:00 p.m. Closing Session ______________________

All session times are EDT.

Day

Session Type

Topic Tracks

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Minisymposium: Evaluating Cancer Genomics from Normal Tissues through Evolution to Metastatic Disease

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Session VMS.ET04.01 – Novel Targets and Therapies

1060 – Genetic and pharmacologic inhibition of Skp2, an E3 ubiquitin ligase and RB1-target, has antitumor activity in RB1-deficient human and mouse small cell lung cancer (SCLC)

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on COVID-19 and Cancer 9:00 AM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on COVID-19 and Cancer 9:00 AM

COVID-19 and Cancer

Introduction

Antoni Ribas
UCLA Medical Center

For other Articles on the Online Open Access Journal on COVID19 and Cancer please see

Opinion Articles from the Lancet: COVID-19 and Cancer Care in China and Africa

Actemra, immunosuppressive which was designed to treat rheumatoid arthritis but also approved in 2017 to treat cytokine storms in cancer patients SAVED the sickest of all COVID-19 patients

The Second in a Series of Virtual Town Halls with Leading Oncologist on Cancer Patient Care during COVID-19 Pandemic: What you need to know

Responses to the COVID-19 outbreak from Oncologists, Cancer Societies and the NCI: Important information for cancer patients

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Minisymposium: Evaluating Cancer Genomics from Normal Tissues through Evolution to Metastatic Disease

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM

1060 – Genetic and pharmacologic inhibition of Skp2, an E3 ubiquitin ligase and RB1-target, has antitumor activity in RB1-deficient human and mouse small cell lung cancer (SCLC)

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Early Detection and ctDNA 1:35 – 3:55 PM

Primary Objectives

Key Secondary Objectives

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on COVID-19 and Cancer 9:00 AM

COVID-19 and Cancer

Introduction

Antoni Ribas UCLA Medical Center

For other Articles on the Online Open Access Journal on COVID19 and Cancer please see

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Symposium New Drugs on the Horizon Part 1 4:50- 6:00 pm

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Drugging Undrugged Cancer Targets 1:30 pm – 5:00 pm

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Signaling in Cancer 11:45am-1:30 pm

SESSION VMS.MCB01.01 – Emerging Signaling Vulnerabilities in Cancer April 27, 2020, 11:45 AM – 1:30 PM Virtual Meeting: All Session Times Are U.S. EDT DESCRIPTION

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks and Clinical Session 11:45am-1:15pm Advances in Cancer Drug Discovery

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks and Clinical Session 9 am

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Live Conference Coverage of AACR 2020 Annual Virtual Meeting; April 27-28, 2020

AACR VIRTUAL ANNUAL MEETING I: SCHEDULE AT A GLANCE

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Antoni Ribas
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SESSION VMS.MCB01.01 – Emerging Signaling Vulnerabilities in Cancer
April 27, 2020, 11:45 AM – 1:30 PM
Virtual Meeting: All Session Times Are U.S. EDT
DESCRIPTION