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2025 PCF TACTICAL Award

Nick James headshot

Unravelling Drivers of Treatment Resistance to PSMA-Lu in Patients with Metastatic Hormone Sensitive Prostate Cancer (mHSPC) and Identification of New Therapeutic Targets to Overcome It

Principal Investigators: Nick James, MBBS, PhD (Institute of Cancer Research), Gerhardt Attard, MD, PhD (University College London Cancer Institute), Hoda Abdel-Aty, MBBS, MD (Royal Marsden Hospital)

Co-Investigators: Noel Clarke, MBBS (Christie Hospital Manchester UK), Jan Taprogge, BS, PhD (Royal Marsden Hospital), Jamshed Bomanji, MBBS, PhD (UCLH NHS Foundation Trust), Edward William Johnston, BS, PhD (Royal Marsden Hospital), Sam Withey, BS, MBBS (Royal Marsden Hospital), Nabil Hujairi, BS, MD (Royal Marsden Hospital), Matthew Blackledge, BS, PhD (Institute of Cancer Research), Glenn Flux, BS, PhD (Royal Marsden Hospital), Yong Du, MBBS, PhD (Royal Marsden Hospital), Mahesh KB Parmar, MSc, PhD (University College London MRC Clinical Trials Unit), Netty Janette Kinsella, RN, PhD (Royal Marsden Hospital), Iain Murray, MSc, PhD (Royal Marsden Hospital), Erik Sahai, BA, PhD (The Francis Crick Institute), Nina Tunariu, MBBS, MD (Royal Marsden Hospital), Anna Clare Wilkins, MBBS, PhD (Institute of Cancer Research), Julia Ruth Murray, MBBS, PhD (Royal Marsden Hospital), Minal Padden-Modi, MBBS (Institute of Cancer Research), Silke Gillessen Sommer, MD (Oncology Institute of Southern Switzerland), Claire Thompson, MBBS, MSc (Institute of Cancer Research), Nicos Fotiadis, MD, PhD (Royal Marsden Hospital), Jean-Philippe Paul Theurillat, MD (Università della Svizzera Italiana), Sarah Howlett, MBBS (UCL Cancer Institute), Yathushan Yogeswaran, BS, MSc (University College London MRC Clinical Trials Unit)

Young Investigators: Emily Grist, MBBS, PhD (University College London), Ashwin Sachdeva, MBBS, PhD (The Christie Hospital NHS Trust), Louise Cerqueira Moreno Carvalho, MD (Hospital Israelita Albert Einstein), Gianmarco Leone, MD, PhD (University College London)

Collaborators: Cristina Müller, PhD, MS (Paul Scherrer Institute), Andrei Gafita, MD (Johns Hopkins University), Siraj Yusuf, MD (Royal Marsden Hospital)

Description:

  • Patients with high-volume metastatic hormone sensitive prostate cancer (mHSPC) rarely exhibit a complete response to treatment even where PSA drops to undetectable levels. New treatments and improved personalized treatment recommendations are urgently needed for these patients, who will otherwise inevitably progress to a state of lethal disease.
  • Dr. James and team hypothesize that residual disease visible on imaging will be representative of the cancer clones that are ultimately lethal, and that by studying these lesions, they can identify genomic and tumor microenvironmental drivers of residual disease and uncover new actionable therapeutic targets. 
  • STAMPEDE2 is a multi-arm, multi-phase clinical trial evaluating the addition of new treatments to current standard of care, for patients with mHSPC. One arm of this trial is testing the addition of 177Lu-PSMA-617 (LuPMSA; Pluvicto®), a radioligand therapy which is approved for metastatic castration-resistant prostate cancer (mCRPC).
  • This TACTICAL Award project will build upon an embedded sub-study in the STAMPEDE2 trial that is using PSMA-PET/CT, whole-body MRI, and SPECT scans to image tumors and evaluate dosimetry (determination of the delivery levels of a radioactive treatment reaching tumors) of 177Lu-PSMA-617.
  • The team will perform detailed per-lesion characterization of differential responses to standard of care +/- 177Lu-PSMA-617, using this imaging data.
  • The team will then undertake targeted biopsies of lesions (both primary and metastatic) that are persistent at the time of best treatment response, and profile these samples to identify factors that contribute to treatment resistance and disease progression. These profiling studies will include in-depth multiplex biological studies to identify drivers and biomarkers of treatment resistance and disease heterogeneity, including genomic features, the tumor microenvironment, and alterations in DNA repair mechanisms. 
  • The team will also integrate gene expression and digital pathology analysis on diagnostic samples with clinical trial data to identify molecular sub-groups that have differential benefit from 177Lu-PSMA-617. 
  • Additionally, they will use this data to identify druggable targets that are drivers of treatment resistance and develop new trials designed to reverse resistance.
  • If successful, this team will develop biological and radiomic biomarkers of treatment resistance to a likely new standard of care treatment (177Lu-PSMA-617), define resistance mechanisms, and identify new therapeutic targets.

What this means to patients: The STAMPEDE2 trial is a multi-arm trial evaluating the addition of new treatments to standard of care for patients with metastatic hormone sensitive prostate cancer (mHSPC). In this TACTICAL Award project, Dr. James and team are using imaging data from the STAMPEDE2 arm testing the addition of 177Lu-PSMA-617 to perform targeted biopsies of residual disease at maximum response to primary therapy, with or without 177Lu-PSMA-617, and perform in-depth imaging, molecular, and pathology-based characterization of these samples to develop biomarkers for treatment selection, and identify drivers of resistance and potential new therapeutic targets for intervention. This could radically improve outcomes for patients with advanced prostate cancer.