• SERB-STAR Fellow
• Ramalingaswami Fellow
• DST-INSPIRE Faculty
• Department of Defense Prostate Cancer Training Award
• Senior Research Fellowship, Council of scientific and industrial research, New Delhi
• Junior Research Fellowship, Indian council of agricultural research, New Delhi.

Broad research activities

I) Rewiring to reverse chemoresistance in Oral Squamous Cell Carcinomas (OSCC)

Chemoresistance is one of the major factor in treatment failure of OSCC. Chemotherapy successfully eliminates the rapidly dividing cells in tumor mass but poorly targets the slowly dividing cells. Due to acquired chemoresistance, the patients experience continued tumor growth with metastatic disease. However, the exact causative factors responsible for it are yet to be explored. The chemoresistance phenotypes can be attributed to reduced apoptosis, enhanced cancer stem cell population, altered metabolic activity and decreased drug accumulation. All these hallmarks are endpoint events when the tumor cells have already acquired drug resistance. Till date, majority of the study engaged in analyzing either the parental drug sensitive cells or late drug resistant cells to understand the molecular mechanism for chemoresistance. However, the intermediate or transition phase of tumor cells (early chemoresistance) during the process of acquired chemoresistance is poorly characterized.

The long term objective to discover the causative factors those play major role in acquiring chemoresistance in OSCC by  characterizing sensitive, early and late resistant cells. Small molecules targeting those causative factors would rewire to reverse chemoresistance in OSCC.

Appropriate model representing sensitive, early and late drug resistant pattern were established using OSCC lines and patient derived cells from clinical samples . Using genomics, proteomics and high through put screening approach, the sensitive, early and late drug resistant cells are being  characterized to discover major drivers of drug resistance in OSCC .

II) Systemic and targeted gene therapy for cancer, targeting anti-apoptotic Bcl-2 family members for effective therapy of oral squamous carcinomas.

Developing an effective systemic and targeted gene therapy for cancer

A major challenge for effective gene therapy is the ability to specifically deliver the therapeutic directly into diseased tissue without exposure to the immune system, particularly with a systemic approach in an immune competent animal model. Progress in gene therapy has been hampered by concerns over the safety and practicality of viral vectors, particularly for intravenous delivery, and the inefficiency of currently available non-viral transfection techniques. We will explore novel targeted-delivery approaches to develop a site-specific delivery and henceforth therapy in immune competent transgenic mouse cancer model. These approaches of systemic gene delivery will facilitate development of efficient, selective and non-toxic modes for gene therapy using therapeutically beneficial genes that offer significant potential to translate into a Phase I/II clinical trial. For therapeutic arms we will explore the tumor suppressor activity of 1) human melanoma differentiation gene-7/Interleukin-24 (mda-7/IL-24) and 2) Suppressor of AP-1 regulated by IFN (SARI) in oral squamous cacinomas. mda-7/IL-24 shows ubiquitous anti tumor effect, its mode of action involves preferential induction of apoptosis in cancer cells while exerting no discernible toxic effects toward normal cells by eliciting unique potent “antitumor bystander activity” as a consequence of autocrine secretion. Similarly, forced expression of SARI resulted in tumor-selective growth inhibition and induction of apoptosis in prostate cancer, malignant glioma and metastatic melanoma cells. Although the precise molecular mechanism by which SARI induces tumor-suppressing activity requires further clarification, preliminary studies revealed that forced expression of SARI resulted in inhibition of DNA binding of activator protein (AP-1) complexes and, consequently, it selectively inhibited AP-1-dependent gene expression. Targeting anti-apoptotic Bcl-2 gene family for effective therapy of Oral squamous carcinomas: Despite intensive investigation, oral cancer remains formidable clinical challenges resulting in high frequencies of morbidity and mortality. Reprogramming tumor cells to undergo programmed cell death (apoptosis) represents a promising and powerful strategy for treating both local and metastatic disease. Ways of achieving this objective involve the selective down regulation of dysregulated oncogenes and/or expression/activation of apoptosis-inducing genes or their products in tumor cells. For example the role of Bcl-2 family members is critical for onset and progression of cancer. Dysregulation of Bcl-2 family members including myeloid cell leukemia-1 (Mcl-1) is often implicated in the acquisition of resistance to apoptosis in malignant cell lines. Mcl-1 plays a pivotal role in cancer cell survival, including that of oral cancer cells, suggesting involvement of this gene in oral squamous carcinogenesis. Over expression of Mcl-1 protects cells from apoptosis induced by a variety of stress-promoting agents. Considering the fact that Mcl-1 is over expressed in the majority of oral cancers, we hypothesize that selectively targeting Mcl-1 alone or in combination with other conventional anti cancer drugs or potential tumor suppressors might provide an effective therapeutic for this metastatic disease.

Publications (best 10)

1. Mohanty S, Mohapatra P, Shriwas O, Ansari SA, Priyadarshini M, Priyadarsini S, Rath R, Sultania M, Das Majumdar SK, Swain RK, Dash R. 2022. CRISPR-based kinome-screening revealed MINK1 as a druggable player to rewire 5FU-resistance in OSCC through AKT/MDM2/p53 axis. Oncogene
2. Mohapatra P, Mohanty S, Ansari SA, Shriwas O, Ghosh A, Rath R, Majumdar SKD, Swain RK, Raghav SK, Dash R. 2022. CMTM6 attenuates cisplatin-induced cell death in OSCC by regulating AKT/c-Myc-driven ribosome biogenesis. FASEB J 36: e22566
3. Mohapatra P, Shriwas O, Mohanty S, Ghosh A, Smita S, Kaushik SR, Arya R, Rath R, Das Majumdar SK, Muduly DK, Raghav SK, Nanda RK, Dash R. 2021. CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3beta axis. JCI Insight 6
4. Shriwas O, Arya R, Mohanty S, Mohapatra P, Kumar S, Rath R, Kaushik SR, Pahwa F, Murmu KC, Majumdar SKD, Muduly DK, Dixit A, Prasad P, Nanda RK, Dash R. 2021. RRBP1 rewires cisplatin resistance in oral squamous cell carcinoma by regulating Hippo pathway. Br J Cancer 124: 2004-16
5. Shriwas O, Priyadarshini M, Samal SK, Rath R, Panda S, Das Majumdar SK, Muduly DK, Botlagunta M, Dash R. 2020. DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m(6)A-demethylation of FOXM1 and NANOG. Apoptosis 25: 233-46
6. Kolapalli SP, Sahu R, Chauhan NR, Jena KK, Mehto S, Das SK, Jain A, Rout M, Dash R, Swain RK, Lee DY, Rusten TE, Chauhan S, Chauhan S. 2021. RNA-Binding RING E3-Ligase DZIP3/hRUL138 Stabilizes Cyclin D1 to Drive Cell-Cycle and Cancer Progression. Cancer Res 81: 315-31
7. Maji S, Shriwas O, Samal SK, Priyadarshini M, Rath R, Panda S, Das Majumdar SK, Muduly DK, Dash R. 2019. STAT3- and GSK3beta-mediated Mcl-1 regulation modulates TPF resistance in oral squamous cell carcinoma. Carcinogenesis 40: 173-83
8. Maji S, Panda S, Samal SK, Shriwas O, Rath R, Pellecchia M, Emdad L, Das SK, Fisher PB, Dash R. 2018. Bcl-2 Antiapoptotic Family Proteins and Chemoresistance in Cancer. Adv Cancer Res 137: 37-75
9. Maji S, Samal SK, Pattanaik L, Panda S, Quinn BA, Das SK, Sarkar D, Pellecchia M, Fisher PB, Dash R. 2015. Mcl-1 is an important therapeutic target for oral squamous cell carcinomas. Oncotarget 6: 16623-37
10. Samal SK, Routray S, Veeramachaneni GK, Dash R, Botlagunta M. 2015. Ketorolac salt is a newly discovered DDX3 inhibitor to treat oral cancer. Sci Rep 5: 9982

	Miss. Pallavi Mohapatra, CSIR-SRF
	Mr. Sibasish mohanty, UGC-SRF
	Miss. Shamima Azma Ansari, UGC-SRF
	Mr. ABINASH BEHERA, CSIR-JRF
	Mr. Devashish Barik, UGC-JRF
	Miss. Khushboo Parveen, CSIR-JRF
	Mr. CHINMAYA ROUT, Lab Technician

Alumni:

PhD

1) Dr. Santanu Maji, Phd, Currently post doc fellow at  VCU medical center, Richmond, Virginia

2) Dr. Sabindra K Samal:  Currently Assistant Professor: BJB autonomous college, Bhubaneswar, Odisha

3) Dr. Omprakash Shriwas:  Currently  Post doc fellow at NIH

4) Dr. Manashi Priyadarshini

RA/Post-doc/Woman Scientist

Dr. Neera Singh

Gene Therapy for Cancer

• DBT sponsored project entitled ‘Investigating the potential tumor suppressive activity of SARI (Suppressor of AP-1 regulated by interferon) in Oral Squamous Cell Carcinomas’ for 3 years (2015-2018).
• DST-SERB sponsored project entitled “Restoring cell death in chemoresistant oral squamous cell carcinomas (OSCC) for 3 years (2016-2019)