Profiling and Eliminating Tumor Subclones Destined for Radioligand Resistance
Abstract
Rationale, Objective, and Aims: Advanced drug-resistant prostate cancer that has spread to other organs, is the second-leading cause of cancer death in the United States. For a limited period, this type of disease can be controlled with targeted therapies that inhibit testosterone signaling, such as Xtandi, Erleada, Zytiga, while taking Lupron. Inevitably however, drug resistance develops, after which the disease becomes much more difficult to control, and requires much strong therapies with many side effects, including chemotherapies. Recently a new class of therapies is being tested in multiple cancers called radioligand therapy; in prostate cancer, the agent is called Lu-PSMA, i.e., radioactive Lutetium bound to a small molecule that targets PSMA on the surface of prostate cancer cells. This is a form of radiation therapy that is administered intravenously once a month. Initially, it is effective in most patients, but it only extends advanced patients’ lives by a median (or middle time) of 4 months. To those ends, we are exploring why Lu-PSMA stops working in many patients after that short time. We have developed a new powerful system called BRUTE, which simulates the hormonal sensitivity of most prostate cancers and can be performed with an intact immune system, unlike many other experimental systems. We are using our BRUTE system and correlative de-identified patient data to identify the molecular pathways that lead to Lu-PSMA to stop working. Once we identify those, we will either use existing drugs to prevent Lu-PSMA resistance, or even develop future versions of Lu-PSMA that can get around such blocks. Next, we use our BRUTE system and correlative de-identified patient data to identify why patients with prostate cancer that has spread to the bone cannot usually have their cancer eradicated. We will try to identify what changes occur within the cancer cells, in response to growing within bone that make it drug resistant. Ultimately, if we could effectively treat bone metastases, or block drug resistance from occurring there, we could prevent much of the suffering associated with prostate cancer. Finally, we examine whether the mechanisms of resistance to drugs such as Xtandi and Lu-PSMA occur in rare prostate cells before exposure to those drugs or whether they predominantly occur after drug exposure. If there are rare pre-existing cells, this means that we could detect them much earlier, and potentially even eradicate them. Applicability of the Research Contributions To FY21 PCRP Overarching Challenges: Directly addresses two challenges (1) by helping define the biology of lethal prostate cancer to reduce death and (2) developing treatments that improve outcomes for men with lethal prostate cancer. Which Patients: Advanced prostate cancer patients who are progressing on targeted therapies, including radioligand such as Lu-PSMA. One part of the study focuses on why we cannot eradicate bone metastases. Potential Clinical Applications, Benefits, Risks: Understanding resistance to radioligands will enable the development of combinatorial or sequential therapies to delay it from occurring. We will also be able to predict which patients may respond the best (or the worst) to it and select therapies accordingly. Projected Time for Patient-Related Outcome: Three years for detection of resistance mechanisms in patients, 4-5 years to set up an investigator-initiated trial to delay resistance using existing FDA-approved drug, and >5 years to develop a novel compound that circumvents existing radioligand pathways. Interim Outcomes: One to three years to identify validated cellular mechanisms of radioligand resistance in murine models, 1-3 years to identify how bone metastases develop resistance, and 1-3 years to identify whether rare drug-resistant cells exist before drug exposure.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310594
Entities
People
- Rohit Bose
Organizations
- United States Army
- University of California, San Francisco