Challenge Awards – Class of 2020

The PCF Challenge Award Winners – Class of 2020 recipients are:


Arul Chinnaiyan, MD, PhD
Arul Chinnaiyan, MD, PhD

2020 Movember – Distinguished Gentleman’s Ride – PCF Challenge Award

Principal Investigators: Arul Chinnaiyan, MD, PhD (University of Michigan), Marcin Cieslik, PhD (University of Michigan), Ulka Vaishampayan, MBBS (University of Michigan), Yuzhuo Wang, PhD (University of British Columbia)

Co-Investigators: Lanbo Xiao, PhD (University of Michigan), Abhijit Parolia, PhD (University of Michigan),  Yuanyuan Qiao, PhD (University of Michigan),  Jeremy Taylor, PhD (University of Michigan),

Project Title: Targeting Transcriptional Addiction in Prostate Cancer by Impeding Neo-Enhancer Accessibility

Description:

  • The androgen receptor (AR) is the primary oncogenic driver in prostate cancer, and thus the primary therapeutic target. However, resistance to androgen deprivation therapy (ADT) and second-generation AR targeting agents like enzalutamide and abiraterone, and progression to metastatic castration resistant prostate cancer (mCRPC), is nearly inevitable. This is because prostate cancer cells commonly adapt mechanisms to maintain AR signaling, such as amplification and mutations of the AR gene.  It has recently been shown that epigenetic changes in the AR gene are also important drivers of the development of mCRPC.
  • Epigenetics is the regulation of the 3D structure of DNA surrounding a gene and its regulatory regions, which causes the gene to be more or less accessible to gene expression machinery.
  • SMARCA2 and SMARCA4 are two major epigenetic regulators that are commonly altered in CRPC, and are required for AR activity. Thus, SMARCA2/4 may be ideal therapeutic targets.
  • Arul Chinnaiyan and team are studying the impact of targeting SMARCA2/4 as a novel treatment approach for mCRPC.
  • The team has previously shown that a novel agent which causes the degradation of SMARCA2/4 has activity against CRPC cells with express AR, but not CRPC cells which do not have AR.
  • In this project, the team will investigate the mechanism of action of the SMARCA2/4-degrader in AR-positive CRPC cells.
  • The team will also investigate the efficacy of the SMARCA2/4-degrader alone and in combination with AR-targeting agents in pre-clinical models of CRPC.
  • The team will identify candidate biomarkers that can identify patients who are more likely to benefit from treatment with the SMARCA2/4-degrader.
  • Finally, the team will initiate a phase 1/2 clinical trial to test the safety and efficacy of the SMARCA2/4-degrader alone and in combination with enzalutamide in patients with mCRPC.

What this means to patients:  Despite recent advances, mCRPC remains an incurable disease state and new treatments are urgently needed.  Dr. Chinnaiyan and team have identified a set of epigenetic regulators, SMARCA2/4, that are important in the development of CRPC and have developed a novel treatment that can target these regulators.  If successful, this team will identify the mechanisms of action of this treatment, and establish efficacy in patients, which may improve outcomes for patients with mCRPC.


Phuoc Tran, MD, PhD
Phuoc Tran, MD, PhD
Kenneth Pienta, MD
Kenneth Pienta, MD

2020 Movember – Distinguished Gentleman’s Ride – PCF Challenge Award

Principal Investigators: Phuoc Tran, MD, PhD (Johns Hopkins University), Kenneth Pienta, MD (Johns Hopkins University)

Co-Investigators: Ana Kiess, MD, PhD (Johns Hopkins University), Hao Wang, PhD (Johns Hopkins University), Alexander Wyatt, PhD (University of British Columbia)

Project Title: Radiolabeled Systemic Therapy with SABR for Castration Sensitive Prostate Cancer Oligometastatic Disease

Description:

  • Oligometastatic prostate cancer is an advanced disease state in which men have fewer than five sites of metastasis, but are still thought to be potentially curable.
  • Phuoc Tran has previously demonstrated that targeting sites of oligometastatic prostate cancer with stereotactic ablative radiation (SABR), a highly focused form of radiation therapy, is feasible and prolongs progression-free survival. However, SABR alone was not curative in most men, and patients often progressed due to outgrowth of tumor deposits, particularly in the bone, that were too small to be detected by molecular imaging at the beginning of the study.
  • Tran and team are conducting two clinical trials in patients with oligometastatic prostate cancer testing whether combining SABR with other systemic radioactive treatments can improve outcomes of patients with oligometastatic prostate cancer. The RAVENs trial will test SABR alone vs. in combination with radium-223. The BLUE JAE trial will test SABR in combination with the PSMA-targeted radionuclide therapy, 177Lu-PSMA.
  • In this project, Dr. Tran and team will use samples from the patients on these trials to investigate whether the levels of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) associate with patient outcomes.
  • Epithelial-mesenchymal transition (EMT) is a phenomenon in which tumor cells change their phenotype to acquire invasive and metastatic properties. Whether low expression of EMT markers is associated with an attenuated metastatic phenotype of oligometastasis and improved outcomes of patients in these trials will be investigated.
  • Immune responses may improve the efficacy of radiation therapy. Whether specific T-cells repertoire at the start of therapy in these trials may impact clinical outcomes will be determined.
  • Finally, the frequency of inherited mutations in DNA repair genes in men with oligometastatic prostate cancer will be determined.
  • If successful, this project will improve the management and understanding of the biology of oligometastatic prostate cancer.

What this means to patients:  Oligometastatic prostate cancer is thought to be a potentially curable state of prostate cancer, in which five or fewer metastases are present. Dr. Tran and team will conduct two clinical trials in men with oligometastatic prostate cancer to test the efficacy of stereotactic ablative radiation (SABR), a highly focused form of radiation therapy combined with other systemic radioactive treatments, and will investigate tumor biology and biomarkers of outcomes in these patients. This may lead to a new, curative treatment paradigm for men with oligometastatic prostate cancer.


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