Research Director: Meena Jhanwar-Uniyal, Ph.D. Associate Professor.
Neuro-oncology Research: Molecular Genetics/Molecular biology.
Understanding the Signaling Pathways involved in relentless growth of GBM
The main focus of the laboratory is to understand the genetic/molecular basis of the regulation of the signaling pathway associated with tumor suppressor genes, particularly PTEN and P53 in Glioblastoma multiforme (GBM), a tumor that is uniformly fatal. The second major theme of our research is to understand the mechanisms by which PI3K/AKT/ mTOR signaling contributes to uncontrolled growth signaling. Further, we have explored small molecule inhibitors of PI3K and mTOR which are showing promising as anti-cancer activity. Seminal findings from our laboratory have suggested that the major cause of ineptitude of mTOR inhibitors in clinic is due to activation of mitogenic pathways via feedback loop. The significance of deregulation of mTOR/S6K signaling in cancer became clear when it was shown to be a major downstream mediator of signaling via the PI3K/AKT axis that is deregulated in a high proportion of human tumors, including GBM. Our research aims to take a range of complimentary cell biology, biochemical and genomic approaches to characterize the role of activation of the pathway in tumorigenesis and to identify key pathways that also contribute to the development of GBM. It is expected that the results of these studies will provide a basis for generation of new therapeutics useful for second-line treatment of GBM.
Characterization of Stem like cells of GBM:
Over the last decade our understanding of biology has made it clear that stem cells play a critical role in the development, growth, as well as, recurrence of tumors, such as GBM. These cancer stem cells (CSCs), like normal stem cells, carry three distinct properties: self-replication, ability to differentiate into multiple lineages, and extensive proliferation. Presence of stem cell marker is associated with poor prognosis. Mutations in tumor suppressor genes, such as PTEN and p53 found in GBM can altered the rate differentiation and maintenance of pluripotency status of these CSC, and making it difficult to treat. We are studying the self-renewal and differentiation of cancer stem cells of brain tumors. We focus on genetic/molecular mechanisms regulating the balance between stem cell self-renewal and differentiation. We hope to understand how CSCs are resistant to therapies, and whether novel mechanism can make them accessible to the therapies. Detailed understanding of the mechanism involved in stem cell regulation will be valuable for the detection and eradication of immortal cancer cells. This knowledge will also be important for the discovery of new therapeutic agents that can prevent dissemination of GBM. We have identified that Akt/mTOR pathway along with MAPK pathway regulate maintenance and differentiation of CSCs.
Medulloblastomas are primary tumors arising in the cerebellum and the most common solid tumor in children. We have shown one of the critical signaling abnormalities is the activation of Akt/mTOR . We address this issue by inhibiting these pathways to curtail migration and growth of tumors. Further, it has been shown that amplification of oncogene Myc is a poor prognostic factor, we observe whether expression of Myc can be altered by pharmacological intervention. We are currently also examining novel genes associated with medulloblastomas. Oncogene Myc overexpression is associated with poor prognosis in medulloblastomas. We are studying the molecular mechanism of regulation of Myc by mTOR pathways.
Identifying genes associated with brain metastasis.
Brain metastasis is the most common cause of mortality and morbidity of many cancers and occurs in more than 40% of patients. Underlying mechanisms of metastatic dissemination to the brain remain to be defined.
The metastatic cascade entails an orderly sequence of steps enabling tumor cells to migrate from the primary tumor and colonize at secondary locations. We have addressed this problem by exploiting the microarray analysis and deciphering the gene pattern that are associated with brain metastasis.
Understanding Metastatic brain tumors.: Pathway dissection and model development
The epithelial to mesenchymal transition (EMT) is a well conserved cellular program that allows polarized, well-differentiated epithelial cells to convert to unpolarized, motile mesenchymal cells. EMT and its converse process, MET (mesenchymal to epithelial transition), are normal developmental processes that plays a critical for appropriate embryogenesis. Tumor progression towards the malignant phenotype requires the loss of the epithelial phenotype and the acquisition of a fibroblastic or mesenchymal one, a reprogramming process such as EMT. Brain metastasis, which occurs in 45% of cancer patients, is a leading cause of cancer morbidity and mortality, conferring an extremely poor prognosis. Role of key players of the EMT, specifically transcription factors, are studied in metastatic brain tumors, by examining the related genes and proteins expression. Furthermore, the contribution of signaling pathways, specifically PTEN/PI3K/mTOR, in regulation of EMT was examined. Our findings indicate that primary tumors, that have a tendency to metastasize to the brain, may go through a cellular reprogramming process known as EMT. Further, we have identified clinically relevant signaling pathway, namely mTOR to mediate the reprogramming.
Stem cell therapy for spinal cord injury.
Spinal cord injury is a major cause of disability in America. Primary spinal cord injury results from direct injury to the spinal cord; secondary injury is a side effect from subsequent edema and ischemia. Current therapies fail to treat the underlying conditions preventing complete recovery. We speculated that stem cell transplant in conjunction with a naturally occurring compound Curcumin longa, a polyphenol that is found in turmeric, will provide better and faster recovery from SCI, with limited to no side effects. Our study showed a strong basis for stem cell therapy along with naturally occurring anti-inflammatory compounds in the treatment of spinal cord injury. Further, this approach may also translate to treatment of spinal cord injury in humans, by utilizing autologous stem cells along with curcumin in the management of this debilitating injury. Our study demonstrated that curcumin stimulated proliferation of stem cells at low doses, but inhibited proliferation in higher doses. Our findings established that recovery from spinal cord injury was noticeably greater in curcumin treated rats. This is the first time it has been shown that stem cell transplant combined with low dose curcumin improved recovery beyond curcumin or stem cell therapy alone.
Dr. Jhanwar-Uniyal's grants