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Posts Tagged ‘KRAS mutation as biomarker for metastatic disease’


New Mutant KRAS Inhibitors Are Showing Promise in Cancer Clinical Trials: Hope For the Once ‘Undruggable’ Target

Curator: Stephen J. Williams, Ph.D.

The November 1st issue of Science highlights a series of findings which give cancer researchers some hope in finally winning a thirty year war with the discovery of drugs that target KRAS, one of the most commonly mutated oncogenes  (25% of cancers), and thought to be a major driver of tumorigenesis. Once considered an undruggable target, mainly because of the smooth surface with no obvious pockets to fit a drug in, as well as the plethora of failed attempts to develop such an inhibitor, new findings with recently developed candidates, highlighted in this article and other curated within, are finally giving hope to researchers and oncologists who have been hoping for a clinically successful inhibitor of this once considered elusive target.

 

For a great review on development of G12C KRas inhibitors please see Dr. Hobb’s and Channing Der’s review in Cell Selective Targeting of the KRAS G12C Mutant: Kicking KRAS When It’s Down

Figure 1Mechanism of Action of ARS853 showing that the inhibitors may not need bind to the active conformation of KRAS for efficacy

Abstract: Two recent studies evaluated a small molecule that specifically binds to and inactivates the KRAS G12C mutant. The new findings argue that the perception that mutant KRAS is persistently frozen in its active GTP-bound form may not be accurate.

 

Although the development of the KRASG12C-specific inhibitor, compound 12 (Ostrem et al., 2013), was groundbreaking, subsequent studies found that the potency of compound 12 in cellular assays was limited (Lito et al., 2016, Patricelli et al., 2016). A search for more-effective analogs led to the development of ARS853 (Patricelli et al., 2016), which exhibited a 600-fold increase of its reaction rate in vitro over compound 12 and cellular activities in the low micromolar range.

 

A Summary and more in-depth curation of the Science article is given below:

After decades, progress against an ‘undruggable’ cancer target

Summary

Cancer researchers are making progress toward a goal that has eluded them for more than 30 years: shrinking tumors by shutting off a protein called KRAS that drives growth in many cancer types. A new type of drug aimed at KRAS made tumors disappear in mice and shrank tumors in lung cancer patients, two companies report in papers published this week. It’s not yet clear whether the drugs will extend patients’ lives, but the results are generating a wave of excitement. And one company, Amgen, reports an unexpected bonus: Its drug also appears to stimulate the immune system to attack tumors, suggesting it could be even more powerful if paired with widely available immunotherapy treatments.

Jocelyn Kaiser. After decades, progress against an ‘undruggable’ cancer target. Science  01 Nov 2019: Vol. 366, Issue 6465, pp. 561 DOI: 10.1126/science.366.6465.561

The article highlights the development of three inhibitors: by Wellspring Biosciences, Amgen, and Mirati Therapeutics.

Wellspring BioSciences

 

In 2013, Dr. Kevan Shokat’s lab at UCSF discovered a small molecule that could fit in the groove of the KRAS mutant G12C.  The G12C as well as the G12D is a common mutation found in KRAS in cancers. KRAS p.G12C mutations predominate in NSCLC comprising 11%–16% of lung adenocarcinomas (45%–50% of mutant KRAS is p.G12C) (Campbell et al., 2016; Jordan et al., 2017), as well as 1%–4% of pancreatic and colorectal adenocarcinomas, respectively (Bailey et al., 2016; Giannakis et al., 2016).  This inhibitor was effective in shrinking, in mouse studies conducted by Wellspring Biosciences,  implanted tumors containing this mutant KRAS.

 

See Wellspring’s news releases below:

March, 2016 – Publication – Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State

February, 2016 – Publication – Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism

Amgen

 

Amgen press release on AMG510 Clinical Trial at ASCO 2019

 

THOUSAND OAKS, Calif., June 3, 2019 /PRNewswire/ — Amgen (NASDAQ: AMGN) today announced the first clinical results from a Phase 1 study evaluating investigational AMG 510, the first KRASG12C inhibitor to reach the clinical stage. In the trial, there were no dose-limiting toxicities at tested dose levels. AMG 510 showed anti-tumor activity when administered as a monotherapy in patients with locally-advanced or metastatic KRASG12C mutant solid tumors. These data are being presented during an oral session at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

“KRAS has been a target of active exploration in cancer research since it was identified as one of the first oncogenes more than 30 years ago, but it remained undruggable due to a lack of traditional small molecule binding pockets on the protein. AMG 510 seeks to crack the KRAS code by exploiting a previously hidden groove on the protein surface,” said David M. Reese, M.D., executive vice president of Research and Development at Amgen. “By irreversibly binding to cysteine 12 on the mutated KRAS protein, AMG 510 is designed to lock it into an inactive state. With high selectivity for KRASG12C, we believe investigational AMG 510 has high potential as both a monotherapy and in combination with other targeted and immune therapies.”

The Phase 1, first-in-human, open-label multicenter study enrolled 35 patients with various tumor types (14 non-small cell lung cancer [NSCLC], 19 colorectal cancer [CRC] and two other). Eligible patients were heavily pretreated with at least two or more prior lines of treatment, consistent with their tumor type and stage of disease. 

Canon, J., Rex, K., Saiki, A.Y. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019) doi:10.1038/s41586-019-1694-1

Besides blocking tumor growth, AMG510 appears to stimulate T cells to attack the tumor, thus potentially supplying a two pronged attack to the tumor, inhibiting oncogenic RAS and stimulating anti-tumor immunity.

 

Mirati Therapeutics

 

Mirati’s G12C KRAS inhibitor (MRTX849) is being investigated in a variety of solid malignancies containing the KRAS mutation.

 

For recent publication on results in lung cancer see Patricelli M.P., et al. Cancer Discov. 2016; (Published online January 6, 2016)

For more information on Mirati’s KRAS G12C inhibitor see https://www.mirati.com/pipeline/kras-g12c/

 

KRAS G12C Inhibitor (MRTX849)

Study 849-001 – Phase 1b/2 of single agent MRTX849 for solid tumors with KRAS G12C mutation

Phase 1b/2 clinical trial of single agent MRTX849 in patients with advanced solid tumors that have a KRAS G12C mutation.

See details for this study at clinicaltrials.gov

 

Additional References:

Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism.

Lito P et al. Science. (2016)

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

Janes MR et al. Cell. (2018)

Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C.

Zeng M et al. Cell Chem Biol. (2017)

Campbell, J.D., Alexandrov, A., Kim, J., Wala, J., Berger, A.H., Pedamallu, C.S., Shukla, S.A., Guo, G., Brooks, A.N., Murray, B.A., et al.; Cancer Genome Atlas Research Network (2016). Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet.48, 607–616

Jordan, E.J., Kim, H.R., Arcila, M.E., Barron, D., Chakravarty, D., Gao, J., Chang, M.T., Ni, A., Kundra, R., Jonsson, P., et al. (2017). Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609.

Bailey, P., Chang, D.K., Nones, K., Johns, A.L., Patch, A.M., Gingras, M.C., Miller, D.K., Christ, A.N., Bruxner, T.J., Quinn, M.C., et al.; Australian Pancreatic Cancer Genome Initiative (2016). Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52.

Giannakis, M., Mu, X.J., Shukla, S.A., Qian, Z.R., Cohen, O., Nishihara, R., Bahl, S., Cao, Y., Amin-Mansour, A., Yamauchi, M., et al. (2016). Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15, 857–865.

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Trovagene’s ctDNA Liquid Biopsy urine and blood tests to be used in Monitoring and Early Detection of Pancreatic Cancer

Reporters: David Orchard-Webb, PhD and Aviva Lev-Ari, PhD, RN

UPDATED on 7/29/2016

Trovagene’s Dual-Sample Liquid Biopsy Performs Well in First Peer-Reviewed Study

https://www.genomeweb.com/trovagenes-dual-sample-liquid-biopsy-performs-well-first-peer-reviewed-study?utm_source=SilverpopMailing&utm_medium=email&utm_campaign=Daily%20News:%20NIH%20Seeks%20New%20Centers%20for%20Precision%20Medicine%20Initiative%20Participant%20Enrollment,%20Management%20-%2007/29/2016%2004:15:00%20PM

Detection and quantitation of ctDNA KRAS mutations from patients with unresectable pancreatic cancer

Inna Chen 1 , Victoria M. Raymond 2 , Jennifer Geis 2 , Sandeep Pingle 2 , Fernando F. Blanco 2 Eric A. Collisson 3 , Vlada Melnikova 2 , Margaret Tempero 3 , Mark G. Erlander 2 , and Julia S. Johansen 1 1Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Denmark; 2Trovagene, Inc, San Diego, California, USA; 3Department of Oncology, University of California San Francisco, California, USA

Conclusions

• This is the largest, prospective dataset exploring ctDNA KRAS in unresectable pancreatic cancer.

• 92.9% of 210 patients with unresectable pancreatic cancer were positive for ctDNA KRAS.

• This detection rate closely matches the published prevalence of KRAS in pancreatic cancer (90%), and out performs previous studies, demonstrating the superior assay sensitivity.

• ctDNA analysis offers a viable tissue biopsy alternative for determining KRAS mutation status, especially in late stage patients.

• ctDNA KRAS analysis identified 52% more patients as positive than CA19-9, demonstrating KRAS as an improved diagnostic tool.

• Individuals with metastatic disease had a 8.2 fold difference in median ctDNA KRAS mutation load at baseline versus a 3.9 fold difference in baseline CA19-9. KRAS may represent an improved biomarker for metastatic disease over CA19-9.

• In two representative patients, dynamic changes in KRAS mutation load were consistent with response by imaging and predicted progressive disease months in advance of progression by imaging.

• Quantitation of KRAS mutant copy load may provide a more informative biomarker for prognosis and monitoring for therapeutic response

http://www.trovagene.com/wp-content/uploads/Posters/20160512%20AACR%20PancreasPoster(1).pdf

 

Trovagene and University of Michigan Enter into Collaboration for Monitoring and Early Detection of Pancreatic Cancer

Trovagene’s KRAS ctDNA liquid biopsy test will be at the forefront of research partnership with Dr. Diane Simeone at University of Michigan Health System

SAN DIEGO, July 6, 2016 /PRNewswire/ — Trovagene, Inc. (NASDAQ: TROV), a developer of circulating tumor DNA (ctDNA) molecular diagnostics, today announced the initiation of a multi-phased collaborative research program with the University of Michigan Comprehensive Cancer Center utilizing the Trovera™ KRAS ctDNA liquid biopsy test.

 

About Pancreatic Cancer and KRAS Mutations

The relative 1-year survival rate for patients with pancreatic cancer is only 28%, and the overall 5-year survival rate is 8%; stage IV pancreatic cancer has a 5-year survival rate of about 1%. At present, surgery offers the only therapeutic means of cure, but less than 20% of patients present with tumors amenable to resection.

The significant mortality rate of pancreatic cancer is due to the high incidence of metastases at the time of diagnosis, its fulminant clinical course, and the lack of adequate systemic therapies. Patients who undergo resection for localized pancreatic carcinoma have a long-term survival of approximately 20% and a median survival of 13 to 20 months. At the other end of the clinical spectrum, a high percentage (40% to 45%) of patients present with unresectable metastatic disease, with a short survival of only 3 to 6 months.

Mutations of the KRAS gene occurs in over 90% of pancreatic carcinomas – no other human tumor comes close in mutational frequency of this particular gene.

SOURCE

http://www.prnewswire.com/news-releases/trovagene-and-university-of-michigan-enter-into-collaboration-for-monitoring-and-early-detection-of-pancreatic-cancer-300294646.html?tc=portal_CAP

http://www.trovagene.com/

 

Other related articles published in this Open Access Online Scientific Journal include the following:

 

 

Hyaluronidase treatment of high HA pancreatic cancer increased progression-free survival

Author: David Orchard-Webb, PhD

https://pharmaceuticalintelligence.com/2016/07/03/hyaluronidase-treatment-of-high-ha-pancreatic-cancer-increased-progression-free-survival/

 

Targeting paclitaxel to the pancreas with a biodegradable drug-eluting device

Author: David Orchard-Webb, PhD

https://pharmaceuticalintelligence.com/2016/07/03/targeting-paclitaxel-to-the-pancreas-with-a-biodegradable-drug-eluting-device/

 

Recent Research On SMAD4 In Pancreatic Cancer

Curator: David Orchard-Webb, PhD

https://pharmaceuticalintelligence.com/2016/06/27/recent-research-on-smad4-in-pancreatic-cancer/

 

Pancreatic Cancer Modeling using Retrograde Viral Vector Delivery and IN-Vivo CRISPR/Cas9-mediated Somatic Genome Editing

Curators: Larry H. Benstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/06/10/pancreatic-cancer-modeling-using-retrograde-viral-vector-delivery-and-in-vivo-crisprcas9-mediated-somatic-genome-editing/

 

Mutations in RAS genes

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/04/23/mutations-in-ras-genes/

 

TP53 tumor Drug Resistance Gene Target

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/12/27/p53-tumor-drug-resistance-mechanism-target/

 

Pancreatic Cancer Targeted Treatment?

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/05/18/pancreatic-cancer-targeted-treatment/

 

Aduro Biotech Phase II Pancreatic Cancer Trial CRS-207 plus cancer vaccine GVAX Fails

Reporter: Stephen J Williams, PhD

https://pharmaceuticalintelligence.com/2016/05/16/aduro-biotech-phase-ii-pancreatic-cancer-trial-crs-207-plus-cancer-vaccine-gvax-fails/

 

The “Guardian Of The Genome” p53 In Pancreatic Cancer

Curator: David Orchard-Webb, PhD

https://pharmaceuticalintelligence.com/2016/05/09/the-guardian-of-the-genome-p53-in-pancreatic-cancer/

 

Targeting Epithelial To Mesenchymal Transition (EMT) As A Therapy Strategy For Pancreatic Cancer

Curator: David Orchard-Webb, PhD

https://pharmaceuticalintelligence.com/2016/04/19/targeting-emt-as-a-therapy-strategy-for-pancreatic-cancer/

 

Pancreatic Cancer at the Crossroads of Metabolism

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/10/13/pancreatic-cancer-at-the-crosroad-of-metabolism/

 

Using CRISPR to investigate pancreatic cancer

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/07/31/using-crispr-to-investigate-pancreatic-cancer/

 

Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Reporter-Curator: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal-transition-in-prostate-cancer-cells/

 

@Mayo Clinic: Inhibiting the gene, protein kinase D1 (PKD1), and its protein could stop spread of this form of Pancreatic Cancer

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/02/24/inhibiting-the-gene-protein-kinase-d1-pkd1-and-its-protein-could-stop-spread-of-this-form-of-pancreatic-cancer/

 

Locally Advanced Pancreatic Cancer: Efficacy of FOLFIRINOX

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/06/01/locally-advanced-pancreatic-cancer-efficacy-of-folfirinox/

 

Consortium of European Research Institutions and Private Partners will develop a microfluidics-based lab-on-a-chip device to identify Pancreatic Cancer Circulating Tumor Cells (CTC) in blood

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/10/consortium-of-european-research-institutions-and-private-partners-will-develop-a-microfluidics-based-lab-on-a-chip-device-to-identify-pancreatic-cancer-circulating-tumor-cells-ctc-in-blood/

 

What`s new in pancreatic cancer research and treatment?

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/10/21/whats-new-in-pancreatic-cancer-research-and-treatment/

 

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

Author: Tilda Barliya, PhD

https://pharmaceuticalintelligence.com/2013/04/11/update-on-pancreatic-cancer/

 

Targeting the Wnt Pathway

Writer and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/04/10/targeting-the-wnt-pathway-7-11/

 

Gene Amplification and Activation of the Hedgehog Pathway

Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/10/29/gene-amplification-and-activation-of-the-hedgehog-pathway/

 

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