Manjeet Rao, PhD
Deputy Director – Greehey CCRI
Co-Leader, Experimental, and Development Therapeutics,
Mays Cancer Center; Discipline Director, Cancer Biology – Graduate Program.
Department: Cell Systems & Anatomy
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.
We actively engage in translational research to discover new, more effective, and safe regimens for cancer treatment. Towards that goal, we recently discovered that an anti-depressant and its derivative could block cancer cell’s ability to repair DNA. Our study became the basis for the clinical trial, which is currently underway.
Another focus of my laboratory is to use microRNAs as novel biomarkers and therapeutics for the diagnosis/prognosis and treatment of pediatric brain tumors and adult cancers. Our recent research achievements of safe and efficacious delivery of microRNA using lipid and FDA-approved nanoparticle-based systemic delivery approaches to treat cancers in the mouse tumor model paves the way for a clinical trial in the near future. In addition to miRNA, using unbiased genome-wide synthetic lethal screens, we have identified novel proteins that play a causal role in tumorigenesis and render cancer cells resistant to cancer treatment drugs. With our expertise in medicinal chemistry, structural biology, silicomodeling, and small molecule screening, we have rationally designed and synthesized several lead small molecules that can interfere with the key residues critical for the activity of those proteins.
We were the first group to design novel algorithms to identify transcriptome-wide methylation and differential RNA methylation in normal and disease conditions. Recently, in a groundbreaking study, we showed that writers, erasers, and readers of RNA methylation cross-talk to maintain a level of RNA methylation critical for the stability of crucial progrowth/proliferation-specific genes. And, any pro-tumorigenic stimulus that perturbs that cross-talk leads to the uncontrolled activity of those genes, resulting in tumor growth and progression. We are currently investigating the role of specific RNA epigenetic modifiers in children’s and adult cancers.
microRNA and Development In addition to cancer, my group have made some seminal discoveries in miRNA and development. We were the first group to develop an in vivoRNA interference (RNAi) approach that mimics the principle by which “microRNAs” are processed (Rao et al., Genes & Dev, 2006). Furthermore, we were the first to show that miRNA plays a critical role in chromatin condensation during germ cell development (Chang et al., PNAS, 2012). Recently, in groundbreaking work we showed that LC3-associated phagocytosis is not only confined to macrophages but is actively used by Sertoli cells to engulf and clear germ cells during germ cell differentiation (Panneerdoss et al., Nature Communications, 2018).
Field of study: Adult and Children’s Cancer; MicroRNA; Small Molecule Inhibitors
Subfield of study: Drug development, Translational Research
Research Areas: Cancer, Epigenetics, Development
Relevant Diseases: Medulloblastoma; Osteosarcoma; Breast Cancer; Glioblastoma
Research Techniques: Mouse tumor models; Ex-vivo explants from cancer patients; Nanoparticle-based drug delivery; RNA-seq; Me-RIP-Seq; PAR-CLIP; Fiber analysis; IHC; Routine Molecular biology techniques
Graduate Research Assistant
Subapriya Rajamanickam, PhD
Panneerdoss Subbarayalu, PhD
Santosh Timilsina, PhD
Graduate Research Assistant
2021Donald G McEwen, Memorial Summer Undergraduate Research Program Student
- Shresth Arya
- Neil Gupta
- Arhan Rao
- Lanka Srilalitha (mentor, Dr. Subbarayalu)
Dr. Rao is actively recruiting graduate students to join his lab.
Dr. Nourhan Abdelfattah, PhD
Postdoctoral Fellow Houston Methodist Research Institute
Dr. J.Saadi Imam, PhD, MD
Postdoctoral Fellow – Residency (MD) Mayo Clinic Jacksonville
Dr. Sanjay Bansal, PhD
Postdoctoral Fellow Bristol-Myers Squibb
Dr. Behyar Zoghi, MD, PhD
Postdoctoral Fellow – Hematologist Methodist Hospital, San Antonio
Dr. Yao-Fu-Chang, PhD
Postdoctoral Fellow Scientific Writer, Dallas
Graduate Student Mirna Therapeutics
Pooja Yadav, PhD
Scientist, Flagship Pioneering
International Journal of Molecular Sciences: A Comprehensive Analysis into the Therapeutic Application of Natural Products as SIRT6 Modulators in Alzheimer’s Disease, Aging, Cancer, Inflammation, and Diabetes (Rao Lab)
Future Focus: San Antonio lands one of its largest Cancer Grants to Bring in New Talent
Manjeet Rao, PhD, Awarded NCI, R01 Grant to Test Efficacy of Novel Drug
- Cells: The RNA Demethylase ALKBH5 Maintains Endoplasmic Reticulum Homeostasis by Regulating UPR, Autophagy, and Mitochondrial Function (Chen, Sung, & Rao Labs) May 17, 2023
- The Gear Up Against Kids Cancer Rides Again! January 20, 2023
- Cancer Letters: The antidepressant imipramine inhibits breast cancer growth by targeting estrogen receptor signaling and DNA repair events (Rao & Chen Labs) May 18, 2022
Rao Lab “In the News.”
Texas Senate Resolution 368: Commending Manjeet Rao for receiving the Presidential Distinguished Junior Research Scholar Award from The University of Texas Health Science Center at San Antonio.