Research Highlights

 

Castration-resistant Prostate Cancer

The vast majority of prostate cancers that are initially hormone dependent and sensitive to androgen deprivation therapy will become resistant to treatment and inevitably relapse as highly aggressive castration-resistant prostate cancers (CRPC). CRPC is a major clinical problem in the disease management of prostate cancer. Multiple mechanisms, including reactivating androgen receptor activity or bypassing androgen dependence, have been reported to be involved in the CRPC development. Although new therapies such as next-generation androgen receptor pathway inhibitors can extend patient survival, further treatment resistance always develops, and CRPC remains a lethal disease in the clinic. There is a critical need to better understand the molecular mechanisms underlying the development and progression of CRPC in order to develop more effective therapies.

Reliable, clinically relevant cancer models are of paramount importance to studying the mechanisms of CRPC and developing new therapeutics. The Living Tumor Laboratory has successfully overcome the major obstacles in developing PDX models from clinical hormone-naïve prostate cancer tissues and has established a number of unique, transplantable hormone-naïve prostate cancer (HNPC) PDX models. These clinically relevant models not only retain the histopathological and molecular characteristics of the parental patients’ tumor, but also recapitulate the clinical disease progression from HNPC to CRPC after host castration and gave rise to castration-resistant tumors. So far we have established seven CRPC PDX sublines from HNPC models. These models showed dramatic androgen receptor signaling changes mirroring the clinical response of prostate cancer to androgen deprivation therapy. These “next-generation” models provide unique tools for studying mechanisms underlying CRPC development, discovering novel therapeutic targets, and assessing treatment efficacy in preclinical drug development.

Neuroendocrine Prostate Cancer

Neuroendocrine prostate cancer (NEPC) is a highly aggressive, lethal subtype of prostate cancer. It generally develops after long-term androgen deprivation therapy of PCa, characterized by small neuroendocrine-like cells which typically express neuroendocrine markers but not androgen receptor or adenocarcinoma markers. Recent advances in the development of more potent androgen receptor pathway inhibitors have led to a dramatic rise in clinical incidence of NEPC. Currently there is no effective target therapy for NEPC. Therefore, new therapeutic targets and more effective treatments are urgently needed to improve the management of the disease.

NEPC research has been hampered by a lack of clinically relevant experimental models of the disease. At the Living Tumor Laboratory, a number of NEPC PDX lines have been derived from clinical NEPC tissues or from hormonal naive adenocarcinoma PDX tissues that underwent neuroendocrine transdifferentiation in mice after castration of the hosts. These models provide clinically relevant and valuable tools for both basic and translation cancer research and have been successfully applied in a wide variety of research activities.

Acidic Tumor Microenvironment

The tumor microenvironment is the cellular and molecular environment in which the tumor exists. Alterations to microenvironmental conditions may promote unrestrained cell proliferation, facilitate tumor initiation, and direct metastasis. The tumor microenvironment has elevated extracellular acidity (pH ~6.5 compared to a physiological pH of 7.4) as a result of cancer metabolism and the overproduction of lactic acid. The acidic tumor microenvironment has profound influences on multiple cancer characteristics including cell proliferation, tissue invasion/metastasis, angiogenesis, treatment resistance, and evasion of immune destruction.

It has been known that elevated glycolysis or increased glutaminolysis in cancer cells can lead to an overproduction of downstream lactic acid. This elevated presence of cancer-generated lactic acid results in the local acidification of the tumor and its surroundings, which is another phenomenon commonly observed in cancer. Lactate and the resultant acidic tumor microenvironment play an active and crucial role in fuelling various fundamental aspects of cancer development and progression. A therapeutic strategy that inhibits the secretion of cancer-generated lactic acid could achieve improved synergistic efficacy as though multiple hallmarks were combinatorially targeted simultaneously.

 

Castration-induced Dormancy of Prostate Cancer

About one third of patients with prostate cancer will experience relapse of the disease years later after initial surgery or radiation for the primary tumor. In cancer dormancy, residual tumor cells exist in either quiescence or a state in which rates of cell proliferation are balanced by those of cell death. During this period, there are no apparent clinical symptoms in patients. Characterization and mechanisms of this stage remain poorly understood, largely due to the difficulty in investigating dormant tumors in patients or the lack of relevant research models.

At the Living Tumor Laboratory, basing on patient-derived prostate cancer xenografts, we have successfully established castration-induced dormancy models of prostate cancer that mimic the time series of precastration, dormant, and relapse stages in clinic. Valuable data generated from these models will provide mechanistic insights into this stage of disease and lead to potential novel therapeutic strategy for disease management.