MiraDx is committed to discovering meaningful ways to better treat cancer in patients with mutations like and including the KRAS-variant
We are developing answers by applying our novel class of functional, germ-line genetic markers in the following areas:
Radiation therapy is a form of cancer treatment that is used in over 2/3 of cancer patients diagnosed every year. Although generally radiation is a safe treatment, 5-10% of patients will experience serious side effects from treatment. In addition, some patients respond not only locally to radiation, but also have an immune response that can help them to fight their cancer. Miradx is at the forefront in this field, with a leading radiogenomics program, applying our class of microRNA binding site mutations to identify patients that respond differently to radiation. Our first publication on this problem found that patients with the KRAS-variant have a weak immune response to radiation, requiring the addition of cetuximab to help (Jama Oncology, 2016).
Cancer systemic therapy
Although it is completely logical that inherited, germ-line genetic differences, present in all cells, including those of the immune system, will predict response and toxicity to developing immune therapies, there has been little study of the genomic areas studied by MiraDx to find such biomarkers. MiraDx discovered a panel of such mutations that predict both response and toxicity to anti-PD1 and anti-PDL1 therapies currently on the market. We are working with potential partners to incorporate these findings into the newer agents to allow better patients selection to achieve improved response and less toxicity from these exciting new therapies. We are additionally working with partners to apply these mutations to all classes of developing immunotherapies. For interested partners, please feel free to contact us at email@example.com.
In addition, we are currently offering the panel to predict toxicity, ImuDx, to physicians interested in this information for better managing their patients. If you would like to join our studies on ImuDx, please contact us at firstname.lastname@example.org.
Head and Neck Squamous Cell Carcinoma
Studies have definitively shown that KRAS-variant head and neck cancer patients respond differently to targeted agents used in standard treatment. Specifically, Cetuximab is an excellent choice for treatment. We are currently working towards additional collaborative studies to better define the time course and dosing, to make this the standard of care for these patients.
Non-Small Cell Lung Cancer
Physicians and researchers at MDACC and Yale University have evaluated the association between treatment response for NSCLC patients in the BATTLE trials and the KRAS-variant. Results from these studies suggest that KRAS-variant patients respond to certain drugs, such as Sorafenib, and not others, such as Gefitinib, used in metastatic lung cancer.
Studies show that standard treatment consisting of Platinum compounds work poorly for ovarian cancer patients with the KRAS-variant. We hope to define the best strategy for these patients, as the KRAS-variant is found in 1 of 4 newly diagnosed ovarian cancer patients.
In collaboration with thought leaders in endometriosis, we are investigating the association between the KRAS-variant and response to the approaches used to manage endometriosis. Results from this ongoing work will help to define the best treatment regimen for KRAS-variant endometriosis patients. Studies are ongoing at mirakind.org.
List of significant published research related to the KRAS-variant:
The KRAS-Variant and miRNA Expression in RTOG Endometrial Cancer Clinical Trials 9708 and 9905
Lee LJ, et al. PLoS One. 2014 Apr 14;9(4):e94167.
Targeted Knock-in of the Polymorphism rs61764370 does not Affect KRAS Expression but Reduces let-7 Levels
Crowley EH et al. Hum Mutat. 2013 Nov 26.
The LCS6 polymorphism in the binding site of let-7 microRNA to the KRAS 3′-untranslated region: its role in the efficacy of anti-EGFR-based therapy in metastatic colorectal cancer patients
Sebio A et al. Pharmacogenet Genomics. 2013 Mar;23(3):142-7.
KRAS-LCS6 genotype as a prognostic marker in early-stage CRC–letter
Ryan BM, et al. Clin Cancer Res. 2012 Jun 15;18(12):3487-8; author reply 3489.
A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis
Grechukhina O., et al. EMBO Mol Med. 2012 Mar;4(3):206-17.
High let-7a microRNA levels in KRAS-mutated colorectal carcinomas may rescue anti-EGFR therapy effects in patients with chemotherapy-refractory metastatic disease
Ruzzo A et al. Oncologist. 2012;17(6):823-9.
SNPing cancer in the bud: MicroRNA and microRNA-target site polymorphisms as diagnostic and prognostic biomarkers in cancer
Salzman & Weidhaas., Pharmacol Therapy, 2012.
The KRAS-variant is associated with risk of developing double primary breast and ovarian cancer
Pilarski et al., PLoS One, 2012.
KRAS alleles: the LCS6 3’UTR variant and KRAS coding sequence mutations in the NCI-60 panel
Kundu ST et al. Cell Cycle. 2012 Jan 15;11(2):361-6.
A KRAS-variant is a Biomarker of Poor Outcome, Platinum Chemotherapy Resistance and a Potential Target for Therapy in Ovarian Cancer
Ratner E. et al. Oncogene. 2011 Dec. 5.
A let-7 microRNA SNP in the KRAS 3′UTR is prognostic in early-stage colorectal cancer
Kim M. Smits et al. Clin Cancer Research, 2011, Oct 12.
MicroRNA signatures differentiate melanoma subtypes
Chan E. et al. Cell Cycle. 2011 Jun1:10(11):1845-52.
KRAS rs61764370 in Epithelial Ovarian Cancer-Letter
Joanne B. Weidhaas and Frank J. Slack. Clinical Cancer Research. Accepted May 31, 2011.
A 3’ untranslated region KRAS variant and triple-negative breast cancer: a case control and genetic analysis
Paranjape T. et al. Lancet Oncology. 2011 Apr;12(4):377-86.
Kras Let-7 LCS6 SNP predicts cetuximab efficacy in KRASwt metastatic colorectal cancer patients: Does treatment combination partner matter?
Zhang W. et al. Ann Oncol. 2011 Feb 22(2):484-5.
Rare BRCA1 haplotypes including 3′UTR SNPs associated with breast cancer risk
Cory Pelletier et al. Cell Cycle 10:1, 90-99; January 1, 2011.
Genetic modulation of the Let-7 microRNA binding to KRAS 3′-untranslated region and survival of metastatic colorectal cancer patients treated with salvage cetuximab-irinotecan
Graziano F et al. Pharmacogenomics J. 2010 Oct;10(5):458-64.
Role of KRAS let-7 LCS6 SNP in metastatic colorectal cancer patients
Ruzzo A et al. Ann Oncol. 2010 Oct 6.
Kras Mutation, KRAS-LCS6 polymorphism, and non-small cell lung cancer
Nelson HH et al. Lung Cancer. 2010 Jul;69(1).
A let-7 microRNA-binding site polymorphism in 3′-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy
Zhang W et al. Ann Oncol. 2010 Jul 5.
A KRAS-variant in ovarian cancer acts as a genetic marker of cancer risk
Ratner E et al. Cancer Res. 2010 Aug 15;70(16):6509-15.
Prevalence of the variant allele rs61764370 T>G in the 3′UTR of KRAS among Dutch BRCA1, BRCA2 and non-BRCA1/BRCA2 breast cancer families
Hollestelle A et al. Breast Cancer Res Treat. 2011 Jul 30.
The KRAS-Variant Genetic Test As a Marker of Increased Risk of Ovarian Cancer
Keane FK and Ratner ES. Rev Obstet Gynecol. 2010 Summer;3(3):118-21.
The BRCA1 3’-UTR: 5711þ421T=T_5711þ1286T=T Genotype Is a Possible Breast and Ovarian Cancer Risk Factor
Malinee Pongsavee et al. GENETIC TESTING AND MOLECULAR BIOMARKERS. Volume 13, Number 3, 2009 Mary Ann Liebert, Inc. Pp. 307-317.
A let-7 microRNA-binding site polymorphism in the KRAS 3′ UTR is associated with reduced survival in oral cancers
Christensen BC et al. Carcinogenesis. 2009 Jun;30(6):1003-7.
A SNP in a let-7 microRNA complementary site in the KRAS 3′ untranslated region increases non-small cell lung cancer risk
Chin LJ, Ratner E et al Cancer Res. 2008 Oct 15;68(20):8535-40.