The VanBrocklin Lab focuses on identifying and validating novel therapeutic targets in melanoma and lung cancer.
The incidence of melanoma has been increasing at an alarming rate over the past twenty years. Approximately 76,250 new cases are expected in 2012 with nearly 9,180 resulting in death. It is the most rapidly increasing malignancy among young people in the United States and is the most common form of cancer in young adults 25-29 years old; over half of the patients are younger than 60 years old. Melanoma accounts for the majority of skin cancer deaths, and prognosis is poor for advanced stages of this disease. Patients with metastatic melanoma have limited treatment options and median survival ranges from 6-10 months. Current FDA-approved drugs for advanced melanoma include interleukin-2, dacarbazine, ipilimumab (anti-CTLA-4) and vemurafenib, but none offer much hope in the way of providing a lifelong cure for most patients.
Therefore, our lab is interested in identifying and understanding the role of molecular alterations frequently observed in melanoma that are vital to promoting tumor survival in order to develop better therapeutic strategies. We are currently investigating the role of c-KIT, NRAS, BRAF and RAL signaling in suppressing apoptosis and promoting tumor initiation and progression using in vitro and in vivo model systems. In addition, we are investigating mechanisms of drug resistance to BRAF and MEK inhibitors in order to develop rational multi-targeted therapeutic approaches that reduce or eliminate acquired resistance observed clinically following significant responses.
Non-Small Cell Lung Cancer (NSCLC)
Lung cancer remains a significant health burden in the US and worldwide. It is responsible for more deaths than breast, colon, and prostate cancer combined. Lung cancer accounts for nearly 30% of all cancer deaths in the US and remains the leading cause of cancer deaths for both men and women. Presently, the five year overall survival rate for NSCLC remains at 15%, while small cell lung carcinoma survival rates are just six percent. It is clear that current therapies are inadequate and targeted agents may provide a more effective treatment option. RAS mutations (KRAS, HRAS or NRAS) are found in approximately one-third of all human malignancies and are highly prevalent in NSCLC. Notably, alterations in KRAS account for 90% of RAS mutations in lung adenocarcinomas. These mutations promote unregulated GTPase activity, leading to constitutive activation of RAS signaling. Alterations in KRAS promote resistance to receptor tyrosine kinase (RTK) directed inhibitors which target upstream components of RAS signaling. Therefore, KRAS or its downstream effectors are attractive candidates for molecular targeted therapeutic strategies. The primary downstream signaling effectors of RAS constitute the mitogen activated protein kinase (MAPK) signaling pathway, the phosphatidylinositol 3-kinase (PI3K)/AKT signaling cascade and the Ras-like Ral GTPases (RALA and RALB). Developing agents that specifically inhibit mutant RAS have proven elusive to date, therefore much attention has focused on targeting downstream MAPK and AKT signaling effectors. Despite the development and evaluation of numerous specific inhibitors of both signaling pathways none have demonstrated clinical efficacy in NSCLC.
Investigation of alternative KRAS effectors in NSCLC resulted in the identification of RALA and RALB as vital components of NSCLC survival and tumorigenicity regardless of KRAS alteration status. We are currently further defining a role for RAL-GTPase signaling in NSCLC and other KRAS-associated tumors and are in the initial stages of developing novel therapeutic agents to inhibit components of this signaling cascade.