Targeting WNT5A-Mediated Therapy Resistance Mechanisms and Tumor Genomic Heterogeneity in Lethal Bone-Metastatic Prostate Cancer
Abstract
I first became aware of the tremendous suffering that bone metastatic prostate cancer causes when my paternal grandfather was diagnosed with it at the age of 82 in 1993. My grandfather was a hero in World War II who rose through the ranks from private to corporal as an anti-aircraft gunner at the front lines along the Rhine in Germany. He was a leader throughout his career in the Postal Service, a dedicated volunteer teacher at the Open University, a classical music enthusiast, and an intrepid world traveler. He survived lung cancer at age 62, though he never smoked, and was highly energetic, jovial, and determined in everything he did. But bone metastatic prostate cancer was a war he could not win, and he died a year after his diagnosis in terrible pain. Although there has been truly remarkable progress made in extending the lives of men with prostate cancer, the development of treatments for bone metastatic prostate cancer lags behind, and there is still no cure. One of the reasons is the difficulty in obtaining samples inaccessible to study bone metastatic prostate cancer and develop models that replicate the disease so that new therapies can be tested. I was very fortunate to collaborate with truly dedicated surgeons here at UCSD, Drs. Kane and Kulidjian, and was able to obtain samples donated by patients from orthopaedic surgeries to repair fractures caused by bone metastatic prostate cancer. These samples have been invaluable, and we have established new models for testing therapies. One of these therapies that we plan to test, Cirmtuzumab, which binds to ROR1, a protein on the surface of the tumor cells and blocks the function of a protein called WNT5A, which has been shown to be involved in bone metastatic prostate cancer. This signaling system is normally active only during embryonic development in the fetus before birth. However, cancer cells can reactivate this signaling system to reacquire the powerful growth and survival properties of embryonic stem cells. These pathways seem particularly potent in bone metastatic cancers. Cirmtuzumab was developed for treating chronic lymphocytic leukemia (CLL) and is now in clinical trials for CLL and metastatic breast cancer. A successful outcome of these studies would be the rapid translation to a clinical trial for Cirmtuzumab in patients with bone metastatic prostate cancer. Next, we will analyze our unique biobank of prostate cancer bone metastasis samples in deep molecular detail to determine all the genes in the genome whose activities are important, not only in the tumor cells, but also in the cells of the bone and bone marrow. This is the first time this can be done in single cells, and it is very important since the bone metastasis samples are a mix of tumor cells, bone marrow, and bone that contains relatively little actual tumor. The majority of the patient bone metastasis samples are comprised of the supporting, non-tumor cells. Therefore, the majority of the gene activities that have been studied in the mixed populations represent the support cells, not the tumor cells. When the metastatic tumor cells start to grow in the bone, they hijack and corrupt the normal cells and turn them into a cancer-supporting environment to the detriment of the normal bone and bone marrow functions that are crucial to the patient. We will be able to distinguish the changes that are in the tumor from the surrounding cells, which up until now has not been possible in the actual bone metastases themselves. We plan to explore these gene signatures for their possible use as biomarkers of prognosis and response to therapy in bone marrow biopsies and to identify new targets for developing novel therapies. The proposed research addresses two of the PCRP 2018 Overarching Challenges: (1) to develop treatments that improve outcomes for men with lethal prostate cancer and (2) to define the biology of lethal prostate cancer to reduce death.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910672
Entities
People
- Christina Jamieson
Organizations
- United States Army
- University of California, San Diego