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Principal Investigator: MATTHEW B RETTIG
Organization: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
Alternative treatment approaches are urgently needed to improve quantity and quality of life of patients
with metastatic castration resistant prostate cancer (mCRPC). Immunotherapy in the form of checkpoint inhibition
has yielded auspicious results in many cancers, including lung cancer, melanoma, renal cell carcinoma, and
lymphoma amongst several others. The frequency of tumor-specific somatic mutations and hence neoantigen
formation strongly predicts for objective response to checkpoint inhibitors (CPIs). Prostate cancer is typified by
a relatively low mutational burden, so it is not surprising CPIs for mCRPC are largely ineffective, although
occasional responses have been observed. Over the last few years, mismatch repair deficiency (dMMR) and
biallelic inactivation of CDK12 (CDK12-/-) have been observed in a small subset of mCRPC patients. Importantly,
these genetic lesions have been associated with increased mutational burden due to increased point mutations
in the case of dMMR and heightened formation of focal tandem duplications in the case of CDK12-/-. Accordingly,
dMMR or CDK12-/- tumors are expected to be sensitive to CPIs.
The frequency of dMMR has been underestimated due to poor sensitivity of detection assays, which can
fail to detect allelic inactivation of MMR genes. Moreover, neither the frequency of dMMR or CDK12-/- nor the
response to checkpoint inhibition or dMMR or CDK12-/- tumors has been studied amongst Veterans. The
relevance of this knowledge gap amongst Veterans is highlighted by key demographic differences in Veterans
compared to the US population at large, which could in principle affect the frequencies of dMMR and CDK12-/-
as well as response to checkpoint inhibition. Using a sensitive next generation sequencing platform and
bioanalytic tool to detect microsatellite instability, a surrogate for dMMR, we predict that we can detect dMMR or
CDK12-/- in at least 15% of Veterans. Furthermore, we hypothesize that Veterans with dMMR or CDK12-/- will
exhibit a high response rate to checkpoint inhibition. We propose three aims:
1. Identify the frequency of dMMR and CDK12-/- as determined by NGS and a sensitive analytic tool for MSI
detection amongst Veterans with mCRPC. The MSI bioanalysis, known as mSINGS (microsatellite instability
by next generation sequencing), as well as targeted gene sequencing inclusive of CDK12 are built-in
components of OncoPlex, one of the CLIA-certified NGS platforms being implemented within the VA
Precision Oncology Program Cancer of the Prostate (POPCAP) network.
2. Perform an open label phase 2 clinical trial of pembrolizumab, an anti-PD1 CPI, to determine the efficacy of
pembrolizumab amongst dMMR and CDK12-/- mCRPC Veterans who have received prior AR signaling
≥
inhibitors. The primary endpoint will be response rate, defined as a composite of: objective response rate by
iRECIST 1.1, PSA50 at 12 weeks, radiographic progression free survival at 6 months.
3. Perform exploratory analyses to identify biomarkers of response and resistance to pembrolizumab in dMMR
and CDK12-/- mCRPC Veterans. For this purpose, we will acquire baseline and at-progression biopsies of
metastases as well as serial blood samples to investigate genomic, transcriptomic, proteomic, and immune
factors that contribute to response.
This study will result in enhanced understanding of the biology of mCRPCs amongst Veterans and the
identification of Veterans who respond to checkpoint inhibition, thereby benefiting from potentially life extending
therapy. In addition, exploratory/correlative analyses could identify molecular targets, the modulation of which
could potentiate the anti-tumor effects of checkpoint inhibition..
Terms: <Affect><Alleles><Allelomorphs><American><Assay><Bioassay><Biological Assay><Biology><Biopsy><Blood Sample><Blood specimen><CLIA accredited><CLIA approved><CLIA certified><CLIA compliant><CLIA licensed><Cancer Cause><Cancer Etiology><Cancer Patient><Cancers><Cell Communication and Signaling><Cell Signaling><Cervical Cancer><Cervix Cancer><Cessation of life><Characteristics><Checkpoint inhibitor><Clinical Treatment Moab><Colon Cancer><Colon Carcinoma><Colorectal Carcinomas><Cyclin-Dependent Kinases><Cyclin-Dependent Protein Kinases><Data><Death><Dedications><Detection><Diagnosis><Drugs><Eligibility><Eligibility Determination><Exhibits><Frequencies><Gene Alteration><Gene Fusion><Gene Mutation><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genome Stability><Genomic Stability><Genomics><Germinoblastic Sarcoma><Germinoblastoma><Grawitz Tumor><Head and Neck Cancer><Head and Neck Carcinoma><Health><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatoma><Hodgkin Disease><Hodgkin Disorder><Hodgkin lymphoma><Hodgkin's><Hodgkin's Lymphoma><Hodgkin's disease><Hodgkins lymphoma><Human><Hypernephroid Carcinoma><Hypernephroma><Immune checkpoint inhibitor><Immune mediated therapy><Immunologic Factors><Immunological Factors><Immunologically Directed Therapy><Immunotherapy><Intracellular Communication and Signaling><K12><K12 Award><K12 Mechanism><K12 Program><Keytruda><Knowledge><Large Bowel Carcinoma><Large Intestine Carcinoma><Learning><Lesion><Life><Liver Cells Carcinoma><Lymphoma><MMR deficiency><Maintenance><Malignant Cervical Neoplasm><Malignant Cervical Tumor><Malignant Head and Neck Neoplasm><Malignant Lymphogranuloma><Malignant Lymphoma><Malignant Melanoma><Malignant Neck Neoplasm><Malignant Neoplasm of the Cervix><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Cervix><Malignant Tumor of the Cervix Uteri><Malignant Tumor of the Lung><Malignant Tumor of the Prostate><Malignant Uterine Cervix Neoplasm><Malignant Uterine Cervix Tumor><Malignant neoplasm of cervix uteri><Malignant neoplasm of lung><Malignant neoplasm of prostate><Malignant prostatic tumor><Medication><Melanoma><Mentored Clinical Scientist Development Program><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Microsatellite Instability><Mismatch Repair><Mismatch Repair Deficiency><Modern Man><Molecular><Molecular Target><Monoclonal Antibodies><Mutation><NGS Method><NGS system><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Neck Cancer><Neoplasm Metastasis><Nephroid Carcinoma><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><ORFs><Open Reading Frames><Patient Selection><Patients><Pharmaceutical Preparations><Phase 2 Clinical Trials><Phase II Clinical Trials><Phenotype><Point Mutation><Population><Post-Replication Mismatch Repair><Primary Neoplasm><Primary Tumor><Primary carcinoma of the liver cells><Progression-Free Survivals><Prospective Studies><Prospective cohort><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate malignancy><Prostatic Cancer><Protein Coding Region><Proteins><Proteomics><Protocol Screening><Pulmonary Cancer><Pulmonary malignant Neoplasm><QOL><Quality of life><Radiography><Renal Adenocarcinoma><Renal Cell Adenocarcinoma><Renal Cell Cancer><Renal Cell Carcinoma><Reporting><Resistance><Reticulolymphosarcoma><Roentgenography><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Site><Somatic Mutation><Transitional Carcinoma><Transitional Cell Carcinoma><Urothelial Carcinoma><Uterine Cervix Cancer><Veterans><alternative treatment><analytical tool><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><anti-tumor effect><antitumor effect><biological signal transduction><biomarker identification><cancer diagnosis><cancer in the colon><cancer metastasis><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><cdk Proteins><check point blockade><check point immunotherapy><check point inhibition><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint blockade><checkpoint immunotherapy><checkpoint inhibition><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><clinical efficacy><detection assay><detection sensitivity><determine efficacy><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><epigenetic gene silencing><epigenetic silencing><evaluate efficacy><examine efficacy><exome><exomes><genome mutation><head/neck cancer><hormone refractory prostate cancer><identification of biomarkers><identification of new biomarkers><immune check point><immune check point blockade><immune check point inhibition><immune check point inhibitor><immune check point therapy><immune checkpoint><immune checkpoint blockade><immune checkpoint inhibition><immune checkpoint therapy><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunogenic><immunologic substance><immunological substance><improved><indel><individualized cancer care><individualized oncology><inhibitor><insertion-deletion><insertion-deletion mutation><insertion/deletion><insertion/deletion mutation><kidney adenocarcinoma><liver carcinoma><lung cancer><mAbs><male><malignancy><malignant head and neck tumor><malignant neck tumor><marker identification><men><military veteran><monoclonal Abs><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><new approaches><next gen sequencing><next generation sequencing><nextgen sequencing><novel approaches><novel strategies><novel strategy><objective response rate><oncology program><open label><open label study><pembrolizumab><personalized oncology><phase 2 study><phase II protocol><phase II study><precision cancer care><precision cancer medicine><precision oncology><predict responsiveness><predicting response><primary end point><primary endpoint><prospective><prostate cancer resistant to androgen><prostate cancer treatment><radiologic imaging><radiological imaging><resistant><response><response biomarker><response markers><sequencing platform><somatic variant><success><tool><transcriptomics><tumor><tumor cell metastasis><veteran population>