Heinric Williams

Epidemiology, pathology, and genetics of prostate cancer among african americans compared with other ethnicities

Prostate cancer is the most common cancer affecting men in the Western world. In the United States, it is the second leading cause of cancer related deaths after lung and bronchus carcinoma. No definitive causes of prostate cancer (PCa) have been identified to date but, increasing age, a positive family history, and sub-Saharan African ancestry are strongly linked to its development. African American men (AAM) have the highest reported incidence rates in the United States and their mortality from the disease is markedly higher than that of European American men (EAM). Conversely, Asian American men and Pacific Islanders (API), American Indian and Alaskan Native (AI/AN) men, and Hispanic men all have lower incidence and mortality rates as compared with EAM. The reasons for these differences are unclear. However, it is clear that AAM have more advanced PCa when diagnosed. Several other reasons have been suggested and these include differences in treatments and health seeking behavior among the ethnic groups, cultural beliefs, environmental/lifestyle factors, dietary and genetic factors. In conclusion, there are multiple factors that impact prostate cancer outcome and that may be responsible for ethnic disparity. These factors are discussed in this chapter.

Combined inhibition of heat shock proteins 90 and 70 leads to simultaneous degradation of the oncogenic signaling proteins involved in muscle invasive bladder cancer

Heat shock protein 90 (HSP90) plays a critical role in the survival of cancer cells including muscle invasive bladder cancer (MIBC). The addiction of tumor cells to HSP90 has promoted the development of numerous HSP90 inhibitors and their use in clinical trials. This study evaluated the role of inhibiting HSP90 using STA9090 (STA) alone or in combination with the HSP70 inhibitor VER155008 (VER) in several human MIBC cell lines. While both STA and VER inhibited MIBC cell growth and migration and promoted apoptosis, combination therapy was more effective. Therefore, the signaling pathways involved in MIBC were systematically interrogated following STA and/or VER treatments. STA and not VER reduced the expression of proteins in the p53/Rb, PI3K and SWI/SWF pathways. Interestingly, STA was not as effective as VER or combination therapy in degrading proteins involved in the histone modification pathway such as KDM6A (demethylase) and EP300 (acetyltransferase) as predicted by The Cancer Genome Atlas (TCGA) data. This data suggests that dual HSP90 and HSP70 inhibition can simultaneously disrupt the key signaling pathways in MIBC.

Dual targeting of HSP70 does not induce the heat shock response and synergistically reduces cell viability in muscle invasive bladder cancer

Muscle invasive bladder cancer (MIBC) is a common malignancy and major cause of morbidity worldwide. Over the last decade mortality rates for MIBC have not decreased as compared to other cancers indicating a need for novel strategies. The molecular chaperones HSP70 and HSP90 fold and maintain the 3-dimensional structures of numerous client proteins that signal for cancer cell growth and survival. Inhibition of HSP70 or HSP90 results in client protein degradation and associated oncogenic signaling. Here we targeted HSP70 and HSP90 with small molecule inhibitors that trap or block each chaperone in a low client-affinity “open” conformation. HSP70 inhibitors, VER155008 (VER) and MAL3-101 (MAL), along with HSP90 inhibitor, STA-9090 (STA), were tested alone and in combination for their ability to reduce cell viability and alter protein levels in 4 MIBC cell lines. When combined, VER+MAL synergistically reduced cell viability in each MIBC cell line while not inducing expression of heat shock proteins (HSPs). STA+MAL also synergistically reduced cell viability in each cell line but induced expression of cytoprotective HSPs indicating the merits of targeting HSP70 with VER+MAL. Additionally, we observed that STA induced the expression of the stress-related transcription factor HSF2 while reducing levels of the co-chaperone TTI1.

MP01-01 COMBINED HEAT SHOCK PROTEIN 90 AND KINASE INHIBITOR THERAPY: INSIGHTS FROM THE CANCER GENOME ATLAS FOR MUSCLE INVASIVE BLADDER CANCER

INTRODUCTION AND OBJECTIVES: The Cancer Genome Atlas (TCGA) for muscle invasive bladder cancer (MIBC) highlights the contribution of kinases and the heat shock protein 90 (HSP90) in the biology of the disease. Small molecule inhibitors of HSP90 (H90Ins) or oncogenic kinases (KI) have shown limited efficacy as monotherapy in clinical trials. This is due to the development of drug resistance resulting in oncogenic reprogramming. Studies in other tumor models have demonstrated that this can be mitigated through combined H90Ins and KI therapy. Therefore, the purpose of this study is to explore the rationale for combined H90Ins and KI therapy in MIBC. METHODS: Using the HSP90 interactome network database, we identified all the HSP90 interacting genes and profiled these genes in the TCGA for MIBC. We determined the number of interactors that were either overexpressed or mutated in MIBC. These results were subjected to gene ontology analysis. Next, we focused on the HSP90 interacting kinases overexpressed in MIBC and identified an up to date set of clinically actionable targets. RESULTS: Over 130 HSP90 interacting genes were mutated or overexpressed in 10% of the 408 MIBC patients in TCGA. The top 4 mutated genes included TTN at 18%, TP53 at 16%, EP300 at 5% and SPTAN1 at 4% of all patients. The top 100 overexpressed genes observed in 11 to 28% of cases included TTI1, YWHAZ, RAF1 and SETBD1. Comparing the number of patients with mutations to gene overexpression suggests that mRNA expression levels may be the more significant driver of disease. From gene ontology analysis, the biology of MIBC appears to involve alterations in macromolecule metabolism and the regulation of nitrogen compounds. Interestingly, when the oncogenic kinases were specifically profiled, all patients overexpressed at least one HSP90 dependent kinase. In over 40% of the cases, more than one HSP90 dependent kinase was overexpressed. Of the HSP90 dependent kinases combined, RAF1, AKT2, EGFR, YES1, GSK3A PRKAA1 and PTK2 were seen in 68% of the cases and represent targets for which drugs are currently available. CONCLUSIONS: While the altered HSP90 gene network have a modest impact on the biology of MIBC, the more profound influence is exerted through the control of the oncogenic kinases involved in the disease. This data strongly supports the use of combination HSP90 and kinase inhibitor therapy in a patient specific and precision medicine model.