Manjeet Rao, Ph.D.
Rank: Associate Professor
Department: Cell Systems & Anatomy
Research in my laboratory is directed towards developing new, more efficacious and less toxic treatments for adult and childhood cancers.
The overall goal of Rao laboratory is to develop more potent and less toxic drugs for treating pediatric and adult cancer patients. The Rao research group employs unbiased high throughput genomewide functional screens as well as small molecular screens to identify novel targets that may play a critical role in pediatric and adult cancer growth, progression and drug sensitivity. We are particularly interested in utilizing microRNAs and small molecule inhibitors as novel therapeutic adjuvants to improve the efficacy of chemotherapy drugs for treating high-risk pediatric brain tumors and triple-negative breast cancers. Another area of our interest involves understanding the role of epigenetic modifiers in cancer development and progression. In addition to cancer, we are interested in understanding the role of microRNA and epigenetic modifiers during development.
microRNA and Development
We were one of the first groups to develop an in vivo RNA interference (RNAi) approach that can be used to silence virtually any gene in a tissue-specific manner. This groundbreaking approach that mimics the principle by which small non-coding RNAs “microRNAs” are processed (Rao et al., Genes & Dev, 2006) laid the groundwork for my research endeavors in microRNA biology at UT Health San Antonio. Research in my laboratory is directed towards understanding the role of microRNAs during development and cancer. Our current projects on miRNAs include (1) understanding the role of miRNA in male germ cell development and differentiation and (2) understanding the role of androgen responsive miRNAs in Sertoli cells.
microRNA and Cancer
Our lab is actively engaged in using microRNAs as novel biomarkers and therapeutic adjuvants for the diagnosis/prognosis and treatment of drug-resistant breast cancers and pediatric brain tumors. Our recent research achievements of safe and efficacious delivery of microRNA using lipid and FDA-approved nanoparticle-based systemic delivery approaches to treat drug-resistant metastatic breast cancers in mouse tumor model paves the way for a phase I clinical trial in the near future. We are in the process of scheduling a pre-IND (Investigational New Drug) meeting with FDA to discuss the required IND-enabling studies before the phase I clinical trial can begin.
We are actively engaged in understanding the role of RNA epigenetics in testicular physiology as well as cancer growth and progression. We have designed a novel algorithm that identifies transcriptome wide methylation as well as differential RNA methylation in normal and disease condition.
Stem (Cancer) Cell
One of our other research interests involves understanding the mechanism by which cancer stem cell self-renewal is regulated. Besides well established gate keeper genetic changes in cancer, epigenetic alterations including global DNA hypomethylation, hypermethylation of specific tumor suppressor genes as well as histone modifications have emerged as common characteristics of many cancers. Recent developments suggesting an epigenetic progenitor origin of human cancers further underscore the importance of epigenetic regulation in tumorigenesis. We believe that the identification and validation of novel molecular targets regulating early epigenetic changes in normal cells will be key to the development of effective therapeutic regimens for treating cancer. To accomplish that we are currently using a loss-of-function RNA interference screen to identify molecular effectors that are in a synthetic lethal relationship with specific polycomb proteins, which are best known as epigenetic regulators and are implicated in the maintenance of normal stem cell pluripotency and the pathogenesis of several human cancers.
microRNA as novel therapeutic adjuvants for treating cancers.
MicroRNAs are small non-coding RNAs that play important roles during normal development and tumorigenesis. Recent miRNA-based clinical trials have begun to establish miRNA therapeutics as a feasible approach for treating diseases in general and cancer in particular. Since miRNAs function through subtle regulation of a large numbers of factors, they represent more attractive targets than the conventional cancer treatments that target single gene or gene products.
Using genomewide screens, we have identified candidate microRNAs” that not only sensitize aggressive breast cancers and high-risk pediatric brain tumors to chemotherapy drugs but also lower the dose of chemotherapy drugs required to kill tumor cells. Our recent research endeavor of achieving safe and efficacious delivery of microRNAs (patent filed) using lipid and FDA-approved nanoparticle-based systemic delivery approaches to treat metastatic breast cancers in mouse tumor model paves the way for phase I clinical trial in near future.
Small molecule therapeutics for treating adult and pediatric cancers.
We have developed several small molecule inhibitors that target factors critical for cancer cell growth and metastasis. Using orthotopic mouse tumor models as well as ex-vivo explants from breast cancer patients, we have recently shown that one of these inhibitors that targets proto-oncogene FOXM1 suppresses cancer growth and metastasis without inducing any toxicity in normal cells. We are currently performing detailed pharmacokinetics/pharmacodynamics studies and exploring the possibility of taking this molecule to clinical trial in near future.
Role of Epigenetic modifiers in cancers.
Besides well established gate keeper genetic changes in cancer, epigenetic alterations including global DNA hypomethylation, hypermethylation of specific tumor suppressor genes as well as histone modifications have emerged as common characteristics of many cancers. However, unlike epigenetic alterations to DNA and histones, which are extensively studied, epigenetic changes to RNA have just begun to capture the imagination of scientific community. Currently, we are studying the role of RNA epigenetic modifications in the growth and progression of acute myeloid leukemia and breast cancers
Identification of novel chemotherapy drug sensitizers.
Chemotherapy is currently the mainstay of systemic treatment for breast cancer patients. However, many patients develop chemo-resistance, leading to early relapse and shorter survival. Moreover, the quality of life for patients who do survive is often substantially reduced due to the toxicity associated with the chemotherapy.
Using unbiased genomewide synthetic lethal screens, we have identified novel proteins that act as potent oncogenes and render cancer cell resistant to cancer treatment drugs. We are in the process of identifying small peptide inhibitors that target these chemotherapy drug modulators.
Role of microRNAs as modulators of chromatin modification during germ cell development.
The spatial and temporal control of protein synthesis in mammalian cells is ensured by checkpoints present at both the transcriptional and translational levels. Using germ cell-specific knockout approach, we recently showed that interaction between microRNAs and actin associated protein sets the stage for an elaborate translational control mechanism that makes sure that protein synthesis occurs in a timely manner and is restricted to target destinations in mammalian cells.
By generating miRNA transgenic mouse model, we are investigating the role of specific microRNAs in chromatin modification during germ cell development and differentiation.
Subapriya Rajamanickam, Ph.D.
Panneerdoss Subbarayalu, Ph.D.
Santosh Timilsina, Ph.D.
Graduate Research Assistant
Graduate Research Assistant
Dr. J.Saadi Imam, Ph.D., M.D.
Postdoctoral Fellow – Residency (M.D.)
Mayo Clinic Jacksonville
Dr. Sanjay Bansal, Ph.D.
Dr. Behyar Zoghi, M.D., Ph.D.
Postdoctoral Fellow – Hematologist
Methodist Hospital, San Antonio
Dr. Yao-Fu-Chang, Ph.D.
Scientific Writer, Dallas