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2024 PCF Challenge Award (Anonymous)

Combination of POLQ inhibitor plus PARP inhibitor for HR-deficient and ATM-deficient Prostate Cancer 

Principal Investigators: Alan D’Andrea, MD (Harvard: Dana-Farber Cancer Institute), Peter Nelson, MD (Fred Hutchinson Cancer Center)

Co-Investigators: Geoffrey Shapiro, MD, PhD (Dana-Farber Cancer Institute), Michael Haffner, MD, PhD (Fred Hutchinson Cancer Center)

Young Investigators: Jacob Berchuck, MD (Dana-Farber Cancer Institute), Stephanie Siegmund, MD (Brigham and Women’s Hospital), Galina Semenova, MD, PhD (Fred Hutchinson Cancer Center)

Collaborators: Bose Kochupurakkal, PhD (Dana-Farber Cancer Institute), Yuna Hirohashi, BS (Dana-Farber Cancer Institute), Roman Gulati, MSc (Fred Hutchinson Cancer Center), Ilsa Coleman (Fred Hutchinson Cancer Center)

Description:

  • BRCA1 and BRCA2 are tumor suppressor genes that are lost in ~13% of metastatic prostate cancer, and are associated with more aggressive and lethal disease. 
  • BRCA1/2 are critical genes that repair damaged DNA. Tumor cells that lose these genes are more aggressive because they more easily gain oncogenic mutations, but at the same time, become highly reliant on related genes, such as PARP, to survive. Thus, targeting PARP is a highly effective way to kill tumor cells that have lost BRCA1/2.  
  • PARP-inhibitors such as olaparib are FDA-approved treatments for patients with several types of cancers that have lost BRCA1/2 or other DNA-repair genes, including metastatic castration resistant prostate cancer (mCRPC). However these treatments are not curative, and not all patients with BRCA-loss tumors respond. 
  • Dr. D’Andrea and team have discovered that BRCA-loss cancer cells are also highly sensitive to inhibitors of POLQ, another related gene that BRCA-loss tumors rely on. 
  • POLQ-inhibitors also killed tumor cells that have lost ATM, a DNA-repair gene similar to BRCA. mCRPC patients with ATM-loss rarely benefit from PARP-inhibitors, meanwhile ATM-loss is common, present in ~11% of advanced prostate cancers.
  • This suggests that POLQ-inhibitors may be a promising alternate treatment approach for patients with these aggressive tumor types. 
  • The team is initiating clinical trials to test a new POLQ-inhibitor, novobiocin, alone or in combination with olaparib, in patients with tumors with deletions in BRCA1/2, ATM and other DNA-repair genes. These trials include a phase 1 trial open to patients with various types of cancers, and a phase 2 trial specifically in patients with mCRPC.
  • In this project, Dr. D’Andrea a team will use data and samples from patients on the novobiocin + olaparib trials to study the mechanisms of action and biological impacts of this combination, and to identify biomarkers to select patients most likely to respond.
  • The team will also evaluate the combination of novobiocin + olaparib in a diverse set of preclinical prostate cancer models, including models that are sensitive and resistant to PARP-inhibitors.
  • If successful, this project will result in a new and more effective precision medicine for patients with several cancer types, including prostate cancer, whose tumors have certain genomic alterations. This could impact up to ~30% of patients with mCRPC, and many more patients with breast, ovarian, pancreatic, and other cancer types where these mutations also occur frequently. 

What this means to patients: Tumors often lose DNA-repair genes such as BRCA1/2 to more easily gain aggressive oncogenic mutations. Dr. D’Andrea and team have found that such tumors are now highly reliant on the POLQ gene, and that inhibiting POLQ can effectively kill these tumor cells. The team is initiating clinical trials to test new POLQ-inhibitors in prostate and other cancer types. In this project, the team will determine how this medication works and how best to use it — in which combinations and in which patients, in order to develop a new precision medicine with maximal impact for patients.