Manjeet Rao, PhD
Deputy Director – Greehey CCRI
Co-Leader, Experimental, and Development Therapeutics,
Mays Cancer Center; Discipline Director, Cancer Biology – Graduate Program.
Rank: Professor
Department: Cell Systems & Anatomy
Office: 4.100.10
Tel: 210-562-9119
raom@uthscsa.edu
The overall goal of my laboratory is to develop more potent and less toxic drugs for treating adult and pediatric cancer patients. We have employed unbiased high throughput genomewide functional screens as well as small molecular screens to identify novel targets that are critical for growth, progression, and drug sensitivity in medulloblastoma and osteosarcoma. In particular, using the loss of function screens, we have identified key genes that play critical/causal roles in the growth and metastasis as well as in the chemo-sensitivity of osteosarcoma. Furthermore, by performing small molecule library screens, we have identified inhibitors of these proteins that may act as novel therapeutics for treating osteosarcoma. Another area of our interest involves understanding the role of RNA epigenetic modifiers in osteosarcoma. In particular, we have identified RNA demethylase as a driver protein that may amplify oncogenic programs in osteosarcoma by regulating DNA replication, DNA repair, and genomic integrity. We aim to develop novel small molecule inhibitors against RNA demethylase that can potentially serve as RNA mimetics, which can abolish the activity of this protein in OS.
Our approach includes a combination of fluorescence polarization-based high-throughput screening using small molecule libraries, cell-based studies, and structure-guided development of novel inhibitors. Towards that goal, we have identified a unique RNA target sequence comprising the core m6 A motif (GGACU) that binds to RNA demethylase with high affinity. Using this unique RNA target sequence, we have performed high-throughput screening of the FDA-approved drug library and identified inhibitors that can potentially inhibit the activity of this driver protein. We are currently testing the efficacy of the inhibitor/s in the PDX model. We plan to explore the possibility of repurposing these drugs in clinical trials in near future.
Our research endeavors have resulted in the clinical development of an anti-depression for treating triple-negative breast cancer patients (Imipramine Before Surgery in Treating Patients with Estrogen Receptor-Positive or Triple Negative Breast Cancer). This study is a perfect example of a bench-to-bedside initiative.
We have identified novel microRNAs that act as a potent tumor suppressors in medulloblastoma. Interestingly, one of these miRNAs sensitizes vincristine as well as radiation response in c-myc amplified medulloblastoma by targeting microtubule dynamics and DNA damage response. We are currently testing the viability of this miRNA in a non-human primate model (in collaboration with Dr. Brigitte Widermann at NCI). We are in the process of scheduling a pre-IND meeting with the FDA to know more about the required IND-enabling studies.
In addition, we are testing the efficacy of this miRNA in the rat leptomeningioma model. The goal is to test whether the miRNA can be delivered via intraventricular injection to avoid any potential immune response or need for a sophisticated delivery vehicle. In the next 3-years, we plan on taking this miRNA to a phase I clinical trial.