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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on AACR Project Genie & Bioinformatics 4:00 PM – 6:00 PM

SESSION VMS.MD01.01 – Advancing Cancer Research through an International Cancer Registry: AACR Project GENIE Use Cases
 
Reporter: Stephen J. Williams, PhD

April 27, 2020, 4:00 PM – 6:00 PM
Virtual Meeting: All Session Times Are U.S. EDT

Session Type
Virtual Minisymposium
Track(s)
Bioinformatics and Systems Biology
17 Presentations
4:00 PM – 6:00 PM
– Chairperson Gregory J. Riely. Memorial Sloan Kettering Cancer Center, New York, NY

4:00 PM – 4:01 PM
– Introduction Gregory J. Riely. Memorial Sloan Kettering Cancer Center, New York, NY

Precision medicine requires an end-to-end learning healthcare system, wherein the treatment decisions for patients are informed by the prior experiences of similar patients. Oncology is currently leading the way in precision medicine because the genomic and other molecular characteristics of patients and their tumors are routinely collected at scale. A major challenge to realizing the promise of precision medicine is that no single institution is able to sequence and treat sufficient numbers of patients to improve clinical-decision making independently. To overcome this challenge, the AACR launched Project GENIE (Genomics Evidence Neoplasia Information Exchange).

AACR Project GENIE is a publicly accessible international cancer registry of real-world data assembled through data sharing between 19 of the leading cancer centers in the world. Through the efforts of strategic partners Sage Bionetworks (https://sagebionetworks.org) and cBioPortal (www.cbioportal.org), the registry aggregates, harmonizes, and links clinical-grade, next-generation cancer genomic sequencing data with clinical outcomes obtained during routine medical practice from cancer patients treated at these institutions. The consortium and its activities are driven by openness, transparency, and inclusion, ensuring that the project output remains accessible to the global cancer research community for the benefit of all patients.AACR Project GENIE fulfills an unmet need in oncology by providing the statistical power necessary to improve clinical decision-making, particularly in the case of rare cancers and rare variants in common cancers. Additionally, the registry can power novel clinical and translational research.

Because we collect data from nearly every patient sequenced at participating institutions and have committed to sharing only clinical-grade data, the GENIE registry contains enough high-quality data to power decision making on rare cancers or rare variants in common cancers. We see the GENIE data providing another knowledge turn in the virtuous cycle of research, accelerating the pace of drug discovery, improving the clinical trial design, and ultimately benefiting cancer patients globally.

 

The first set of cancer genomic data aggregated through AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) was available to the global community in January 2017.  The seventh data set, GENIE 7.0-public, was released in January 2020 adding more than 9,000 records to the database. The combined data set now includes nearly 80,000 de-identified genomic records collected from patients who were treated at each of the consortium’s participating institutions, making it among the largest fully public cancer genomic data sets released to date.  These data will be released to the public every six months. The public release of the eighth data set, GENIE 8.0-public, will take place in July 2020.

The combined data set now includes data for over 80 major cancer types, including data from greater than 12,500 patients with lung cancer, nearly 11,000 patients with breast cancer, and nearly 8,000 patients with colorectal cancer.

For more details about the data, analyses, and summaries of the data attributes from this release, GENIE 7.0-public, consult the data guide.

Users can access the data directly via cbioportal, or download the data directly from Sage Bionetworks. Users will need to create an account for either site and agree to the terms of access.

For frequently asked questions, visit our FAQ page.

  • In fall of 2019 AACR announced the Bio Collaborative which collected pan cancer data in conjuction and collaboration and support by a host of big pharma and biotech companies
  • they have a goal to expand to more than 6 cancer types and more than 50,000 records including smoking habits, lifestyle data etc
  • They have started with NSCLC have have done mutational analysis on these
  • included is tumor mutational burden and using cbioportal able to explore genomic data even further
  • treatment data is included as well
  • need to collect highly CURATED data with PRISM backbone to get more than outcome data, like progression data
  • they might look to incorporate digital pathology but they are not there yet; will need good artificial intelligence systems

 

4:01 PM – 4:15 PM
– Invited Speaker Gregory J. Riely. Memorial Sloan Kettering Cancer Center, New York, NY

4:15 PM – 4:20 PM
– Discussion

4:20 PM – 4:30 PM
1092 – A systematic analysis of BRAF mutations and their sensitivity to different BRAF inhibitors: Zohar Barbash, Dikla Haham, Liat Hafzadi, Ron Zipor, Shaul Barth, Arie Aizenman, Lior Zimmerman, Gabi Tarcic. Novellusdx, Jerusalem, Israel

Abstract: The MAPK-ERK signaling cascade is among the most frequently mutated pathways in human cancer, with the BRAF V600 mutation being the most common alteration. FDA-approved BRAF inhibitors as well as combination therapies of BRAF and MEK inhibitors are available and provide survival benefits to patients with a BRAF V600 mutation in several indications. Yet non-V600 BRAF mutations are found in many cancers and are even more prevalent than V600 mutations in certain tumor types. As the use of NGS profiling in precision oncology is becoming more common, novel alterations in BRAF are being uncovered. This has led to the classification of BRAF mutations, which is dependent on its biochemical properties and affects it sensitivity to inhibitors. Therefore, annotation of these novel variants is crucial for assigning correct treatment. Using a high throughput method for functional annotation of MAPK activity, we profiled 151 different BRAF mutations identified in the AACR Project GENIE dataset, and their response to 4 different BRAF inhibitors- vemurafenib and 3 different exploratory 2nd generation inhibitors. The system is based on rapid synthesis of the mutations and expression of the mutated protein together with fluorescently labeled reporters in a cell-based assay. Our results show that from the 151 different BRAF mutations, ~25% were found to activate the MAPK pathway. All of the class 1 and 2 mutations tested were found to be active, providing positive validation for the method. Additionally, many novel activating mutations were identified, some outside of the known domains. When testing the response of the active mutations to different classes of BRAF inhibitors, we show that while vemurafenib efficiently inhibited V600 mutations, other types of mutations and specifically BRAF fusions were not inhibited by this drug. Alternatively, the second-generation experimental inhibitors were effective against both V600 as well as non-V600 mutations. Using this large-scale approach to characterize BRAF mutations, we were able to functionally annotate the largest number of BRAF mutations to date. Our results show that the number of activating variants is large and that they possess differential sensitivity to different types of direct inhibitors. This data can serve as a basis for rational drug design as well as more accurate treatment options for patients.

  • Molecular profiling is becoming imperative for successful  targeted therapies
  • 500 unique mutations in BRAF so need to use bioinformatic pipeline; start with NGS panels then cluster according to different subtypes or class specific patterns
  • certain mutation like V600E mutations have distinct clustering in tumor types
  • 25% of mutations occur with other mutations; mutations may not be functional; they used highthruput system to analyze other V600 braf mutations to determine if functional
  • active yet uncharacterized BRAF mutations seen in a major proportion of human tumors
  • using genomic drug data found that many inhibitors like verafanib are specific to a specific mutation but other inhibitors that are not specific to a cleft can inhibit other BRAF mutants
  • 40% of 135 mutants were functionally active
  • USE of Functional Profiling instead of just genomic profiling
  • Q?: They have already used this platform and analysis for RTKs and other genes as well successfully
  • Q? how do you deal with co reccuring mutations: platform is able to do RTK plus signaling protiens

4:30 PM – 4:35 PM
– Discussion

4:35 PM – 4:45 PM
1093 – Calibration Tool for Genomic Aggregates (CTGA): A deep learning framework for calibrating somatic mutation profiling data from conventional gene panel data. Jordan Anaya, Craig Cummings, Jocelyn Lee, Alexander Baras. Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, MD, Genentech, Inc., CA, AACR, Philadelphia, PA

Abstract: It has been suggested that aggregate genomic measures such as mutational burden can be associated with response to immunotherapy. Arguably, the gold standard for deriving such aggregate genomic measures (AGMs) would be from exome level sequencing. While many clinical trials run exome level sequencing, the vast majority of routine genomic testing performed today, as seen in AACR Project GENIE, is targeted / gene-panel based sequencing.
Despite the smaller size of these gene panels focused on clinically targetable alterations, it has been shown they can estimate, to some degree, exomic mutational burden; usually by normalizing mutation count by the relevant size of the panels. These smaller gene panels exhibit significant variability both in terms of accuracy relative to exomic measures and in comparison to other gene panels. While many genes are common to the panels in AACR Project GENIE, hundreds are not. These differences in extent of coverage and genomic loci examined can result in biases that may negatively impact panel to panel comparability.
To address these issues we developed a deep learning framework to model exomic AGMs, such as mutational burden, from gene panel data as seen in AACR Project GENIE. This framework can leverage any available sample and variant level information, in which variants are featurized to effectively re-weight their importance when estimating a given AGM, such as mutational burden, through the use of multiple instance learning techniques in this form of weakly supervised data.
Using TCGA data in conjunction with AACR Project GENIE gene panel definitions, as a proof of concept, we first applied this framework to learn expected variant features such as codons and genomic position from mutational data (greater than 99.9% accuracy observed). Having established the validity of the approach, we then applied this framework to somatic mutation profiling data in which we show that data from gene panels can be calibrated to exomic TMB and thereby improve panel to panel compatibility. We observed approximately 25% improvements in mean squared error and R-squared metrics when using our framework over conventional approaches to estimate TMB from gene panel data across the 9 tumors types examined (spanning melanoma, lung cancer, colon cancer, and others). This work highlights the application of sophisticated machine learning approaches towards the development of needed calibration techniques across seemingly disparate gene panel assays used clinically today.

 

4:45 PM – 4:50 PM
– Discussion

4:50 PM – 5:00 PM
1094 – Genetic determinants of EGFR-driven lung cancer growth and therapeutic response in vivoGiorgia Foggetti, Chuan Li, Hongchen Cai, Wen-Yang Lin, Deborah Ayeni, Katherine Hastings, Laura Andrejka, Dylan Maghini, Robert Homer, Dmitri A. Petrov, Monte M. Winslow, Katerina Politi. Yale School of Medicine, New Haven, CT, Stanford University School of Medicine, Stanford, CA, Stanford University School of Medicine, Stanford, CA, Yale School of Medicine, New Haven, CT, Stanford University School of Medicine, Stanford, CA, Yale School of Medicine, New Haven, CT

5:00 PM – 5:05 PM
– Discussion

5:05 PM – 5:15 PM
1095 – Comprehensive pan-cancer analyses of RAS genomic diversityRobert Scharpf, Gregory Riely, Mark Awad, Michele Lenoue-Newton, Biagio Ricciuti, Julia Rudolph, Leon Raskin, Andrew Park, Jocelyn Lee, Christine Lovly, Valsamo Anagnostou. Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, Memorial Sloan Kettering Cancer Center, New York, NY, Dana-Farber Cancer Institute, Boston, MA, Vanderbilt-Ingram Cancer Center, Nashville, TN, Amgen, Inc., Thousand Oaks, CA, AACR, Philadelphia, PA

5:15 PM – 5:20 PM
– Discussion

5:20 PM – 5:30 PM
1096 – Harmonization standards from the Variant Interpretation for Cancer Consortium. Alex H. Wagner, Reece K. Hart, Larry Babb, Robert R. Freimuth, Adam Coffman, Yonghao Liang, Beth Pitel, Angshumoy Roy, Matthew Brush, Jennifer Lee, Anna Lu, Thomas Coard, Shruti Rao, Deborah Ritter, Brian Walsh, Susan Mockus, Peter Horak, Ian King, Dmitriy Sonkin, Subha Madhavan, Gordana Raca, Debyani Chakravarty, Malachi Griffith, Obi L. Griffith. Washington University School of Medicine, Saint Louis, MO, Reece Hart Consulting, CA, Broad Institute, Boston, MA, Mayo Clinic, Rochester, MN, Washington University School of Medicine, Saint Louis, MO, Washington University School of Medicine, Saint Louis, MO, Baylor College of Medicine, Houston, TX, Oregon Health and Science University, Portland, OR, National Cancer Institute, Bethesda, MD, Georgetown University, Washington, DC, The Jackson Laboratory for Genomic Medicine, Farmington, CT, National Center for Tumor Diseases, Heidelberg, Germany, University of Toronto, Toronto, ON, Canada, University of Southern California, Los Angeles, CA, Memorial Sloan Kettering Cancer Center, New York, NY

Abstract: The use of clinical gene sequencing is now commonplace, and genome analysts and molecular pathologists are often tasked with the labor-intensive process of interpreting the clinical significance of large numbers of tumor variants. Numerous independent knowledge bases have been constructed to alleviate this manual burden, however these knowledgebases are non-interoperable. As a result, the analyst is left with a difficult tradeoff: for each knowledgebase used the analyst must understand the nuances particular to that resource and integrate its evidence accordingly when generating the clinical report, but for each knowledgebase omitted there is increased potential for missed findings of clinical significance.The Variant Interpretation for Cancer Consortium (VICC; cancervariants.org) was formed as a driver project of the Global Alliance for Genomics and Health (GA4GH; ga4gh.org) to address this concern. VICC members include representatives from several major somatic interpretation knowledgebases including CIViC, OncoKB, Jax-CKB, the Weill Cornell PMKB, the IRB-Barcelona Cancer Biomarkers Database, and others. Previously, the VICC built and reported on a harmonized meta-knowledgebase of 19,551 biomarker associations of harmonized variants, diseases, drugs, and evidence across the constituent resources.In that study, we analyzed the frequency with which the tumor samples from the AACR Project GENIE cohort would match to harmonized associations. Variant matches increased dramatically from 57% to 86% when broader matching to regions describing categorical variants were allowed. Unlike precise sequence variants with specified alternate alleles, categorical variants describe a collection of potential variants with a common feature, such as “V600” (non-valine alleles at the 600 residue), “Exon 20 mutations” (all non-silent mutations in exon 20), or “Gain-of-function” (hypermorphic alterations that activate or amplify gene activity). However, matching observed sequence variants to categorical variants is challenging, as the latter are typically only described as unstructured text. Here we describe the expressive and computational GA4GH Variation Representation specification (vr-spec.readthedocs.io), which we co-developed as members of the GA4GH Genomic Knowledge Standards work stream. This specification provides a schema for common, precise forms of variation (e.g. SNVs and Indels) and the method for computing identifiers from these objects. We highlight key aspects of the specification and our work to apply it to the characterization of categorical variation, showcasing the variant terminology and classification tools developed by the VICC to support this effort. These standards and tools are free, open-source, and extensible, overcoming barriers to standardized variant knowledge sharing and search.

https://cancervariants.org/

  • store information from different databases by curating them and classifying them then harmonizing them into values
  • harmonize each variant across their knowledgebase; at any level of evidence
  • had 29% of patients variants that matched when compare across many knowledgebase databases versus only 13% when using individual databases
  • they are also trying to curate the database so a variant will have one code instead of various refseq codes or protein codes
  • VIC is an open consortium

 

 

5:30 PM – 5:35 PM
– Discussion

5:35 PM – 5:45 PM
1097 – FGFR2 in-frame indels: A novel targetable alteration in intrahepatic cholangiocarcinoma. Yvonne Y. Li, James M. Cleary, Srivatsan Raghavan, Liam F. Spurr, Qibiao Wu, Lei Shi, Lauren K. Brais, Maureen Loftus, Lipika Goyal, Anuj K. Patel, Atul B. Shinagare, Thomas E. Clancy, Geoffrey Shapiro, Ethan Cerami, William R. Sellers, William C. Hahn, Matthew Meyerson, Nabeel Bardeesy, Andrew D. Cherniack, Brian M. Wolpin. Dana-Farber Cancer Institute, Boston, MA, Dana-Farber Cancer Institute, Boston, MA, Massachusetts General Hospital, Boston, MA, Brigham and Women’s Hospital, Boston, MA, Dana-Farber Cancer Institute, Boston, MA, Dana-Farber Cancer Institute, Boston, MA, Broad Institute of MIT and Harvard, Cambridge, MA, Massachusetts General Hospital, Boston, MA

5:45 PM – 5:50 PM
– Discussion

5:50 PM – 6:00 PM
– Closing RemarksGregory J. Riely. Memorial Sloan Kettering Cancer Center, New York, NY

 

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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

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

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

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 KRASG12C or KRASG12D 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, NF1Null 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

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

Follow on Twitter at:

@pharma_BI

@AACR

@GenomeInstitute

@CureCancerNow

@UCLAJCCC

#AACR20

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#curecancernow

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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. 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

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

Follow on Twitter at:

@pharma_BI

@AACR

@GenomeInstitute

@CureCancerNow

@UCLAJCCC

#AACR20

#AACR2020

#curecancernow

#pharmanews

 

 

 

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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

For more on @pharma_BI and LPBI Group Conference Coverage in Real Time please go to

https://pharmaceuticalintelligence.com/press-coverage/

and

 

 

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AACR and Dr. Margaret Foti Announce Free Virtual Annual Meeting for April 27, 28 2020 and other Free Resources

Reporter: Stephen J. Williams, PhD

Please see the following email from Dr. Foti and the AACR on VIRTUAL MEETING to be conducted April 27 and 28, 2020.

This is truly a wonderful job by AACR.  In a previous posting I had considered the need for moving international scientific meetings to an online format which would make the information available to a wider audience as well as to those who don’t have the opportunity to travel to a meeting site.  At @pharma_BI we will curate and live tweet the talks in order to enhance meeting engagement, as part of the usual eConference Proceedings we do.

Again Great Job by the AACR!

Dear Colleagues,

We hope you are staying safe and well and are adjusting to the challenges of the COVID-19 global pandemic. During this crisis, we remain steadfast in supporting our members and our mission.

I am pleased to announce a number of actions that we are taking to disseminate innovative cancer science and medicine to the global cancer research community:

  • AACR Virtual Annual Meeting 2020: Selected Presentations. We were excited to receive more than 225 clinical trials for presentation at the Annual Meeting. Due to the time-sensitive nature of these trials—many of which are practice-changing—we are making them available to the community at the time of the original April meeting. Therefore, as per our recent announcement, the AACR will host a slate of selected sessions online featuring these cutting-edge data.
This Virtual Annual Meeting will be held on April 27 and 28, 2020, and will include more than 30 oral presentations in several clinical trial plenary sessions along with commentaries from expert discussants, as well as clinical trial poster sessions consisting of short videos providing the authors’ perspectives. The Virtual Meeting will feature a New Drugs on the Horizon session as well as nine minisymposia that will showcase a broad sample of basic and translational science. Topics will include genomics, tumor microenvironment, novel targets, drug discovery, therapeutics, immunotherapy, biomarkers, and cancer prevention. A special minisymposium titled “Advancing Cancer Research Through an International Cancer Registry” will feature use cases of data available through AACR Project GENIE.

This Virtual Meeting will be available free to everyone, although attendees will be asked to register to participate. The session and presentation titles for the Virtual Meeting, as well as a link to the registration site, will be posted to the AACR website by Monday, April 13.

  • Release of Abstracts. All of the abstracts scheduled for presentation in the Virtual Meeting—and any other clinical trial abstracts that are scheduled for presentation at the rescheduled meeting—will be posted online on Monday, April 27. All other abstracts that have been accepted for presentation at the rescheduled meeting will be posted online on Friday, May 15.
  • AACR Annual Meeting 2019: Free Webcast Presentations. The complete webcasts of the AACR Annual Meeting are typically made freely available 15 months after the conclusion of the meeting. However, we have made these webcast presentations available free effective immediately, so that you can review the most compelling science from the Annual Meeting 2019 which was held in Atlanta.
  • Free Access to AACR Journals. To ensure that all members of the cancer research community have access to the information they need during this challenging time, we have opened access to our nine highly esteemed journals effective today through the end of the virtual meeting. Please be sure to visit the AACR journals webpage for journal highlights, and to sign-up for eTOC alerts.
  • Rescheduled AACR Annual Meeting. We are planning to reschedule the Annual Meeting for late August while at the same time closely monitoring the developments surrounding COVID-19. An official announcement of the rescheduled meeting will be made in the near future.

We hope that these plans will enable you to continue your important work during this global health crisis. Thank you for all you do to accelerate progress against cancer, and thank you for your loyalty to the AACR.

Sincerely,
Margaret Foti, PhD, MD (hc)
Chief Executive Officer
American Association for Cancer Research

 

For more information on Virtual Meetings please see

Is It Time for the Virtual Scientific Conference?: Coronavirus, Travel Restrictions, Conferences Cancelled

and  REAL TIME conference coverage at https://pharmaceuticalintelligence.com/press-coverage/

and other article and e-conference proceedings on this Online Open Access Journal

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