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Your search keyword '"Sander B. Frank"' showing total 2 results
Start Over Author "Sander B. Frank" Publisher american society for clinical investigation
2 results on '"Sander B. Frank"'

1. Genomic attributes of homology-directed DNA repair deficiency in metastatic prostate cancer

Author

Navonil De Sarkar, Sayan Dasgupta, Payel Chatterjee, Ilsa Coleman, Gavin Ha, Lisa S. Ang, Emily A. Kohlbrenner, Sander B. Frank, Talina A. Nunez, Stephen J. Salipante, Eva Corey, Colm Morrissey, Eliezer Van Allen, Michael T. Schweizer, Michael C. Haffner, Radhika Patel, Brian Hanratty, Jared M. Lucas, Ruth F. Dumpit, Colin C. Pritchard, Robert B. Montgomery, and Peter S. Nelson

Subjects
Oncology, Medicine
Abstract

Cancers with homology-directed DNA repair (HRR) deficiency exhibit high response rates to poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy. Though mutations disrupting BRCA1 and BRCA2 associate with HRR deficiency (HRRd), patterns of genomic aberrations and mutation signatures may be more sensitive and specific indicators of compromised repair. Here, we evaluated whole-exome sequences from 418 metastatic prostate cancers (mPCs) and determined that one-fifth exhibited genomic characteristics of HRRd that included Catalogue Of Somatic Mutations In Cancer mutation signature 3. Notably, a substantial fraction of tumors with genomic features of HRRd lacked biallelic loss of a core HRR-associated gene, such as BRCA2. In this subset, HRRd associated with loss of chromodomain helicase DNA binding protein 1 but not with mutations in serine-protein kinase ATM, cyclin dependent kinase 12, or checkpoint kinase 2. HRRd genomic status was strongly correlated with responses to PARPi and platinum chemotherapy, a finding that supports evaluating biomarkers reflecting functional HRRd for treatment allocation.

Published
2021
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2. Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damage

Author

Elahe A. Mostaghel, Colin C. Pritchard, Emmanuel S. Antonarakis, Jun Luo, Payel Chatterjee, Peter S. Nelson, Robin Tharakan, Michael T. Schweizer, Jared M. Lucas, Michael D. Nyquist, Hung-Ming Lam, Eva Corey, Ilsa Coleman, Sander B. Frank, and Samuel R. Denmeade

Subjects
musculoskeletal diseases, 0301 basic medicine, Male, DNA damage, DNA repair, medicine.drug_class, Poly ADP ribose polymerase, Resting Phase, Cell Cycle, 03 medical and health sciences, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, PARP1, Medicine, Humans, Cellular Senescence, BRCA2 Protein, business.industry, Gene Amplification, Prostatic Neoplasms, General Medicine, medicine.disease, Androgen, G1 Phase Cell Cycle Checkpoints, Androgen receptor, stomatognathic diseases, 030104 developmental biology, chemistry, Receptors, Androgen, 030220 oncology & carcinogenesis, PC-3 Cells, Cancer research, Androgens, Growth inhibition, Poly(ADP-ribose) Polymerases, business, Research Article, DNA Damage
Abstract

Prostate cancer (PC) initially depends on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with antitumor activity. SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks, G(0)/G(1) cell-cycle arrest, and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA, which was augmented by poly (ADP-ribose) polymerase 1 inhibition. SPA-induced double-strand breaks were accentuated in BRCA2-deficient patients with PC, and combining SPA with poly (ADP-ribose) polymerase or DNA-dependent protein kinase inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from patients with PC receiving SPA as part of ongoing phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to patients with PC who have AR amplification or DNA repair deficiency and for combining SPA therapy with poly (ADP-ribose) polymerase inhibition.

Published
2019

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