Research Interest

Multiple Myeloma

Despite the arsenal of developed and FDA-approved anti-cancer drugs, cancer is still a leading cause of death. The limiting factor in treating cancers is no longer solely drug availability, but now also includes the need for more comprehensive diagnostic approaches. Biochemical factors that cause tumors to develop and progress vary from one cancer to another, as well as from one patient to another. Personalized cancer care requires treatment that specifically targets biomolecules defining a given tumor, based on knowledge of the tumor’s molecular features. Our recent advances in genomics and proteomics in multiple myeloma (MM) have increased our understanding of disease pathogenesis, helped to identify novel therapeutic targets, and provided the scientific rationale for combining targeted therapies to increase tumor-cell cytotoxicity and abrogate drug resistance. Specifically, gene microarray profiling has shown major differences between normal plasma cells and cells from monoclonal gammopathy of unclear significance (MGUS) and MM cells, with further modulations within MM cells and in cells progressing to plasma cell leukemia. Therefore, we have profiled individual patients newly diagnosed with MM in order to tailor targeted therapy for them; it is likely that cocktails of therapeutics will be needed to overcome resistance. Recognition of the role of the bone marrow (BM) milieu in conferring growth, survival, and drug resistance in MM cells - in both the laboratory and in animal models - has enabled us to establish a new treatment paradigm targeting the tumor cell and its microenvironment. Our studies in a SCID-human mouse model of MM have demonstrated modulations associated with binding of MM cells to the BM microenvironment: upregulation of growth-, survival-, and drug-resistance genes in MM cells; increased adhesion molecule expression on MM cells and bone marrow stromal cells (BMSCs); and increased cytokine transcription and secretion in BMSCs. Thalidomide, the proteasome inhibitor bortezomib, and the novel immunomodulatory drug lenalidamide maintain their cytotoxicity against MM cells even in the BM milieu. They do so by: (1) directly inducing apoptosis of drug-resistant MM cells; (2) decreasing the adhesion of MM cells to BMSCs and extracellular matrix proteins; (3) downregulating the transcription and secretion of cytokines in the BM milieu that mediate tumor cell growth, survival, and migration. Each of these drugs has been shown to have antitumor activity in relapsed and refractory MM, whether alone or combined with dexamethasone. Clinical trials have also evaluated their utility earlier in the disease course. Finally, our correlative gene profiling, proteomic, and signaling studies in tumor cell samples from patients treated with novel agents have identified the mechanisms of sensitivity and resistance, provided the rationale for selection of patients most likely to respond, helped to design combination therapies to enhance sensitivity and overcome resistance in MM cells, and suggested ways to develop more potent, selective, and less toxic targeted therapeutics.

Brain Tumour

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that remains invariably fatal. Despite improved diagnostics, surgical procedures and the advent of targeted therapies, therapeutic options for GBM are few and prognosis has remained largely unchanged over the last several decades. Our research is focused on the use of high-throughput screening of chemical compounds and pharmacologic libraries to identify novel, small molecules that are cytotoxic to brain tumor cells. The PI3K/Akt/mTOR pathway is frequently deregulated in GBM and represents a promising therapeutic target. Class Ia phosphoinositide 3-kinases (PI3Ks) mediate cell and tissue growth downstream of growth Factors, insulin, IGF-1, RTKs and oncogenes. With several novel inhibitors of PI3-K/Akt in active clinical development, this application will explore potential shortcomings of these agents in an effort to identify strategies to maximally therapeutically exploit drugs targeting this critical signaling pathway. The PI3K/Akt/mTOR pathway is frequently deregulated in GBM to promote tumor growth and represents a promising target for novel therapeutic approaches. To identify agents that target PI3K pathway-driven cancers, we designed a panel of structurally diverse drug-like molecules to target this pathway. High- throughout screening then identified those compounds that arrested proliferation in a dose- dependent manner in a number of glioma cell lines. Hypoxia regulates events involved in cancer initiation, progression, drug resistance and metastasis. Hypoxia is linked to drug resistance, tumor recurrence and poor outcome. Hence, there is an urgent, unmet need to develop models that reflect the hypoxic tumor microenvironment as well as novel, effective therapeutics based upon the biology of disease that kill brain cancer cells. The identification, translational development and clinical assessment of agents that target hypoxia-adaptations cytotoxic to brain cancer cells will improve GBM patient outcome. To address this problem, we have developed a sophisticated model system that co-cultures brain tumor cells with astrocytes under normoxic and hypoxic conditions. The concept that novel PI3K/Akt inhibitors can overcome prosurvival hypoxic adaptations within the hypoxic microenvironment and reduce the growth of brain cancer cells has not been rigorously addressed. The rationale for developing hypoxia-driven therapeutics is based upon the premise that key adaptations occur that control cellular growth and eventually provide therapeutic benefit. We have developed a unique, sophisticated model of the brain tumor microenvironment that incorporates glioma cells co-cultured with astrocytes under normoxic or hypoxic conditions. Molecular signals that drive tumor formation and maintenance commonly overlap with those involved in normal development and wound responses – two processes in which normal stem cells function. It is therefore not surprising that cancers invoke stem cell programs that promote tumor malignancy. Stem cell-like cancer cells (or cancer stem cells) need not be derived from normal stem cells but may be subjected to evolutionary pressures that select for the capacity to self renew extensively or differentiate depending on conditions. Current cancer model systems may not fully recapitulate the cellular complexity of cancers, perhaps partially explaining the lack of power of these models in predicting clinical outcomes. New methods are enabling researchers to identify and characterize cancer stem cells.