Mechanisms of Melanoma Progression
Malignant melanoma is one of the most aggressive types of human cancers. Currently, the median survival time of metastatic melanoma patients is approximately 8.5 months. In the skin, melanoma often originates from nevi which represent benign aggregates of senescent (permanently arrested) melanocytes. Thus, melanomas that originate from nevi must have developed mechanisms to overcome senescence, and these mechanisms are largely unknown. Recently, my lab has established that the overexpression of oncogenic transcription factor C-MYC significantly suppresses senescence in normal melanocytes. Reciprocally, the depletion of C-MYC in human metastatic melanoma cells re-activated dormant senescence programs, indicating that C-MYC is continuously required for the suppression of senescence during melanoma progression. The mechanisms that are required for the suppression of senescence by C-MYC in normal human melanocytes and melanoma cells are currently being pursued in my laboratory.
Invasion is one of the most detrimental features of melanoma. During the past several years, we found that C-MYC positively regulates melanoma cell invasion, although the mechanisms are not known. These mechanisms are also being investigated in my lab.
Novel Agents for Melanoma Therapy
The poor prognosis of metastatic melanoma has been associated with exceptional resistance of this malignancy to available antineoplastic treatments, ranging from immunological approaches to radio- or chemotherapy. Thus, the development of novel anti-melanoma agents is a high priority for melanoma treatment. Elevated expression of the oncogene C-MYC has been associated with advanced stages of melanoma in several studies, including ours. By performing a multi-step screening of complex small molecule libraries, we have identified several compounds that efficiently and specifically suppress MYC-dependent transcriptional regulation in cells from all tested human tumor lines including metastatic melanomas. Moreover, one compound substantially decreased the growth of human melanoma xenografts in nude mice without any apparent side effects. Further development of the identified compounds into anti-melanoma chemotherapeutic agents is being pursued in my laboratory.
KLF9 - Novel Transcriptional Regulator of Multiple Myeloma Chemotherapy Resistance
Multiple myeloma (MM) is a plasma cell disorder that accounts for approximately 10% of all hematologic malignancies. Although the introduction of novel agents in the past decade has increased the median overall survival of myeloma patients from 30 months to 45-72 months, the disease remains incurable. One such agent, bortezomib (Velcade®, PS-341), significantly increased overall survival in patients with relapsed or refractory multiple myeloma. Bortezomib suppresses proteosomal degradation leading to substantial changes in cellular transcriptional programs and ultimately resulting in apoptosis. Transcriptional regulators that are required for bortezomib-induced apoptosis in MM cells are largely unknown.
Recently, our lab has discovered that a member of Kruppel-like family of transcription factors, KLF9, regulates bortezomib-induced apoptosis in MM cells. Suppression of KLF9 also induced resistance to another anti-myeloma agent, novel histone deacetylase inhibitor LBH589. We have shown that basal KLF9 levels are higher in MM cells from patients that responded to bortezomib compared to non-responders. Thus, KLF9 appears to be an important factor for drug-resistance in multiple myeloma. Molecular mechanisms of KLF9 functioning in MM and other blood malignancies are currently being studied in my laboratory.