Human nuclear receptors (NRs) are a family of 48 transcription factors that play critical roles in many diseases including cancer. Published studies implicated few NRs such as estrogen receptor (ER), androgen receptor (AR) in cancer progression and drugs targeting ER and AR are widely used for treating cancer. However, therapy resistance occurs over a period of time to these therapies and is a significant clinical problem.
Recent advances in cancer genomics uncovered novel roles of NR-mediated signaling in tumor development and identified the role of several additional members of NR as molecular drivers in women cancers. Although, there is significant heterogeneity of NR signaling, individual NRs may physiologically function as molecular drivers and therapeutic strategies targeting the activity of multiple NRs may have significant utility in breast and ovarian cancers.
It is very critical to understand how specific NRs crosstalk with oncogenic drivers and how they contribute to cancer progression and therapy resistance. NRs are ideal candidates for therapeutic intervention as they are highly dysregulated in cancer, have well defined ligand binding domains and interacting proteins, thus make them amenable targets for drug development. The focus of Dr. Vadlamudi's research to utilize preclinical models to understand the molecular basis of NR signaling that contribute to progression of women cancers and other diseases.
Current research interests include: (1) identification and characterization of novel NRs that contributes to breast and ovarian cancer progression (2) characterizing the function and mechanism of NR-coregulators in therapy resistance (3) developing transgenic and knock-out mouse models for studying NR signaling in cancer and neuronal diseases (4) development of small molecular inhibitors targeting NRs for treating advanced breast and ovarian cancers.
Cortez V, Samayoa C, Zamora A, Martinez L, Tekmal RR, Vadlamudi RK. PELP1 overexpression in the mouse mammary gland results in the development of hyperplasia and carcinoma. Cancer Research, 2014 Dec 15;74(24):7395-405. PMID: 25377474. http://cancerres.aacrjournals.org/content/74/24/7395.long
Krishnan SR, Nair BC, Sareddy GR, Saha Roy S, Natarajan M, Suzuki T, Peng Y, Raj G, and Vadlamudi RK. Novel role of PELP1 in regulating a chemotherapy response in MTp53-expressing TNBC cells. 2015, Breast Cancer Research and Treatment, 150(3):487-99. http://www.ncbi.nlm.nih.gov/pubmed/25788226
Sareddy GR, Li X, Liu J, Viswanadhapalli S, Garcia L, Gruslova A, Cavazos D, Garcia M, Strom AM, Gustafsson JA, Tekmal RR, Brenner A, Vadlamudi RK. Selective Estrogen Receptor β Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma. Sci Rep. 2016 Apr 29;6:24185. doi: 10.1038/srep24185. PubMed PMID: 27126081. http://www.nature.com/articles/srep24185
Raj G, Sareddy GR, Ma S, Lee TK, Viswanadhapalli S, Li R, Liu X, Murakami S, Chen C, Lee W, Mann M, Krishnan SK, Manandhar B, Gonugunta V, Strand D, Tekmal R, Ahn J, and Vadlamudi RK. Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers. Elife. 2017 Aug 8;6. pii: e26857. doi: 10.7554/eLife.26857.https://elifesciences.org/articles/26857