Manjeet Rao, PhD

  • Rank: Associate Professor
  • Department: Cell Systems & Anatomy
  • Office: 4.100.10
  • Location: Greehey CCRI
  • Tel: 1.210.562.9119

 

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 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.

 


Figure 1: Therapeutic potential of IB-12

Live bioluminescence images of mice injected with vehicle or small molecule inhibitor IB-1-nanoparticle show complete response in IB-1-treated mice. Lung tumor metastasis volume was assessed starting from day 8 until animals were sacrificed at day 36 after breast cancer cell introduction.

 

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.

 

 

Manjeet Rao, Ph.D., joined the Greehey Children's Cancer Research Institute in January of 2007 with major faculty responsibilities as a Principal Investigator in Molecular Oncogenesis and Associate Professor in the Department of Cellular and Structural Biology. Dr. Rao completed his post-doctoral research at The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA. Dr. Rao pioneered the in vivo RNA-interference (RNAi) approach that can be used to silence virtually any gene in a tissue-specific manner. The simplicity of his RNAi approach will facilitate the generation of mouse models mimicking human conditions caused by various degrees of genetic hypomorphism, such as ectodermal dysplasia, T-cell immunodeficiency, autosomal dominant polycystic kidney diseases, and various types of cancer. Selective expression of siRNAs may be crucial to effective therapy, as undesired toxicity is a major problem of gene therapy.

 

 

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.

RNA epigenetics
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.

 

 

Federal


Funding Agency NIH/NCI
Title R01 CA179120-01A1 : MicroRNAs: Safe and effective therapeutic adjuvants for treating triple negative breast cancers.
Status Active Active
Period 02/2015-01/2020
Role Principal Investigator
Grant Detail To test the hypothesis that miRNAs are effect therapeutic adjuvants to treat drug resistant triple negative breast cancers.

Funding Agency NIH/NCI
Title R03 HD078654-01 : Importance of Androgen regulated miRNAs in male fertility.
Status Active Active
Period 07/2014-06/2016
Role Principal Investigator
Grant Detail To goal of this project is to elucidate the role of microRNA as novel androgen-responsive transcription factor in the Sertoli cells.

Funding Agency NIH (NIGMS)
Title R01 GM113245-0: Graphic models for global RNA methylation
Status Active Active
Period 9/2014-6/2017
Role Co-Principal Investigator
Grant Detail The goal of this project is to develop, for the first time, computational graphical models to enable 1) accurate and reproducible detection of global mRNA methylations, and 2) context-specific differential RNA methylations in normal and in cancer.

Funding Agency National Cancer Institute
Title Cancer Biology Training Grant
Status Active Active
Period 8/2011-7/2016
Role Contributor
Grant Detail The goal of the Cancer Biology Training Program is to educate the next generation of cancer researchers to meet the growing demands for scientists trained in the multiple facets of cancer biology. This training program is uniquely poised to train minority students because of our rich cultural heritage in South Texas. Trainees will be selected for their academic excellence and their dedication to cancer research.

Funding Agency NIH
Title miRNA-adjuvants: Safe and effective therapeutic for treating drug resistant TNBCsy
Status Active Active
Period 2/2015-1/2020
Role Principal Investigator

Funding Agency NCI/NIH
Title U54 CA113001-10: Role of RNA methylation in breast cancer growth and progression.
Status Active Active
Period 7/2014-2/2016
Role Co-Principal Investigator
Grant Detail The major goal of this project is to identify differential RNA methylation in breast cancer cells.

Private

Funding Agency Voelcker Fund
Title Voelcker Foundation: Improving the efficacy of chemotherapy drugs for treating breast cancers.s
Status Active Active
Period 7/2013-6/2016
Role Principal Investigator
Grant Detail The major goal of this grant is to investigate the mechanism of drug resistance in triple negative breast cancer and potential role of miRNAs in this process.

Funding Agency Owens Foundation
Title William and Ella Owens Foundation research grant: MicroRNA as novel therpeutic adjuvants to treat drug resistant breast cancers
Status Active Active
Period 1/2013-12/2015
Role Co-Principal Investigator

State

Funding Agency CPRIT
Title RP140594: microRNAs: safe and effective therapeutic adjuvants for treating drug resistant breast cancers.
Status Active Active
Period 8/2014-8/2015
Role Principal Investigator
Grant Detail To test the hypothesis that miRNAs are effect therapeutic adjuvants and prognostic markers to treat breast cancers.

 

 

11.2013 - TV news documentary: News 4 ran a story on our groundbreaking research

Websites that highlight our breakthrough

07.2013 - Special invitation from the President of Society for the Study of Reproduction (SSR) to give a special seminar at 46th Annual meeting of SSR , Montreal, Quebec.

2013 - UT Health San Antonio, Presidential Junior Research Scholar Award:
The Presidential Distinguished Junior Research Scholar Award honors one young investigator at The UT Health San Antonio each year who has made a major contribution to research, has earned extramural support and has generated national recognition for their outstanding achievements.

04.2006 - Best poster award (and Honorary mention), MD Anderson Cancer Center,
Fellows day

02.2005 - Institutional research award, MD Anderson Cancer Center

04.2003 - Special Odyssey Fellow Award, MD Anderson Cancer Center: This award is given to fellows with outstanding scientific achievements. This award was supported by The Houston Endowment Inc.

01.2001 - Recipient of a Trainee Travel Award for the International conference on epididymis, Charlottesville, VA.

01.1997 - Special Fellow Award, Department of Biotechnology, Government of India

01.1994 - Senior Research Fellowship: Council of Scientific and Industrial Research (CSIR), Government of India

01.1992 - Junior Research Fellowship: Council of Science and Industrial Research (CSIR), Government of India

 

 

  • Dr. J.Saadi Imam, Ph.D; MD (Postdoctoral Fellow) – Residency (MD) Mayo Clinic Jacksonville
  • Dr. Sanjay Bansal, Ph.D (Postdoctoral Fellow) – Bristol-Myers Squibb
  • Dr. Behyar Zoghi, MD; Ph.D (Postdoctoral Fellow – Hematologist, Methodist Hospital,
    San Antonio
  • Dr. Yao-Fu-Chang, Ph.D (Postdoctoral Fellow) – Scientific Writer, Dallas
  • Jason Plyler (Graduate Student) - Mirna Therapeutics