Defining the Molecular Basis for the Immunogenicity of ADT-Resistant Locally Advanced Prostate Tumors
Abstract
Rationale, Objective, and Aims of the Application: About 15-20% of all patients diagnosed with localized prostate cancer are considered high-risk. This means that there is a higher probability that after surgery or radiation, their cancer will come back. These numbers are based on historical averages of patients with specific clinical diagnostic criteria, such as higher Gleason scores in their biopsy sample. Patients generally recur due to hidden micrometastases that are present at the time of initial therapy—these are not detected by even the most sensitive of imaging, and because they are outside the prostate, neither radiation nor surgery treats them. Neoadjuvant therapy, in which drugs are given prior to surgery or radiation, certainly has effects on prostate-localized disease, but is believed to also act on those hidden micrometastases. In our clinical trials, we have evaluated moving hormonal therapies earlier in the disease course to the neoadjuvant setting, and they are tremendously effective in about 40% of patients with otherwise high-risk disease. Of course, the question then becomes why didn’t 60% of patients respond well? We have examined the biopsy and posttreatment specimens from patients in our study. First, we found that patients who respond poorly always have at least some immune infiltration around the cancer that is left in the prostate. This is remarkable because untreated prostate cancer with immune infiltration is extremely rare. Second, we found that, in patients whose cancers do not respond completely to neoadjuvant hormone therapy, there is a genetic signature that predicts that they would have also responded to HER2-targeting therapies, a class of drugs that is safe and effective in patients with certain types of breast and ovarian cancer. The first objective of this application is to study tissue samples from patients who have immune infiltration in their cancer after treatment, and ask what genomic or genetic features of the tumor correlate with that. The second objective of this application is to use freshly-acquired prostate tumor specimens from patients receiving radical prostatectomies to test whether those tumors can be killed by adding immunotherapy (specifically PDL1 blockade), HER2 inhibition, or both, to hormone therapy. Thus, our application has two aims. The first aim is to characterize the immunology of posttreatment tumors and how they compare to untreated tumors from the same patient, with a goal of understanding the relationship between genetics and immune response. The second aim is to test validate our findings using drug studies of patient tissue samples in mice. We are using a mouse xenograft protocol that also uses cord blood derived stem cells enabling us to study an immune response in the mouse that is matched to the patient. Ultimate Applicability of the Research: Likely contributions of the study to the FY22 PCRP overarching challenges. This study addresses two of the PCRP overarching challenges. First, locally advanced prostate cancer will progress to lethal cancer in about 60% of patients, even with aggressive neoadjuvant therapies. The patients in our study have been diagnosed with NCCN high-risk disease. Thus, this project responds to the challenge to develop treatments that improve outcomes for men with lethal prostate cancer. Second, we are making an effort to define the biology of prostate cancer progression to lethal prostate cancer to reduce death. Our application responds to this challenge by developing a greater understanding of how these lethal cancers evade intense androgen deprivation and what can promote an immune response, making them more sensitive to immunotherapy. Types of Patients This Project Will Help and How It Will Help Them: This project will help patients with newly diagnosed disease that currently has a very unfavorable prognosis – high-risk, with a significant change of recurrence if treated by surgery or radia
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310318
Entities
People
- Haydn Kissick
Organizations
- Emory University
- United States Army