PRAVEEN KUMAR NEELI

My research during PhD was focused on understanding cancer progression and the genes that are responsible for the growth and metastasis of breast and prostate cancers. I discovered a new variant of an oncogene MTDH, aptly named MTDHΔ7 in Triple-negative breast cancers and investigated its role in breast cancer progression for the first time (Neeli PK et al., Oncogene 2020). Moreover my research delved into intricate epigenetic regulation of MTDH in TNBC cells (Neeli et al., FEBS 2022). Intrigued by the potential of repurposed drugs as anti-cancer agents, I explored the anti-cancer effects of Type-2 diabetic drug Metformin and the AMPK activator AICAR on TNBCs (FEBS J 2015). I investigated on the genes responsible for multidrug resistance in prostate cancer and found the beneficial role of statins in the treatment of prostate cancers (Molecular Carcinogenesis 2019). I was involved in development of Mitochondrial-targeted drug named Mito-Esc. This remarkable compound not only demonstrated promise in preventing age-associated atherosclerosis (Atherosclerosis 2022) but also emerged as a potential anti-cancer agent (Chemcomm 2021). The significance of Mito-Esc was recognized with the filings of patents (US-2022296618-A1, WO-2022254405-A1) and its recent licensing by India's top pharma company, SunPhama Pvt Limited, India for commercial use. After my PhD I joined Prof. Yong Li lab at Baylor College of Medicine, USA as a postdoc. I had the privilege of contributing to the development of CD38 CAR-T therapy for lymphoid malignancies (JECCR 2022). I was involved in developing DNA vaccines, small molecule inhibitors for mutant p53 (Genes and Diseases, Frontiers in oncology 2023). During pandemic, I involved in designing a Spike-based Covid-19 DNA vaccine that has demonstrated a comparable immunogenicity with a leading mRNA vaccine (Neeli et al., iScience 2023). I am currently developing DNA vaccines for multiple cancer types. In summary I have published 18 research and review papers, and two patents in my credit including one patent licensed. Methodical [Subject] Postdoctoral Associate familiar with specimen and data handling, documentation compliance and study ethics. Experienced in classroom instruction, faculty collaboration and project support.

1. Received Indian Counsil of Medical Research (ICMR) Fellowship in 2014 for a period of 5 years

2. Qualified GATE-2014 Examination with 97 percentile

3. Qualified CSIR-NET 2014 and AP-SET 2014 for lectureship in Universities/ Colleges.

4. Collaborated with team of scientists in the development of Mito-Esc, an anti-cancer agent which is patented, licensed to a MNC.

5. Presented a Poster at a National Conference on “ADVANCED CANCER THERAPEUTICS (ACT-2016)” April 4-6 at CSIR-IICT, Hyderabad, India. Paper entitled “ Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: Relevance in age-associated vascular dysfunction.

6. Presented a Poster at International Conference on Advances in Chemical Biology and Biologic's (ICACB-2019)” Feb 28-March 2 at CSIR-IICT Hyderabad, India. Paper entitled “Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: Relevance of statins in chemosensitization”

7. Participated in American Association of Cancer research (AACR-2023) Annual Meeting at Orlando, USA (April14-19, 2023).

8. Oral presentation at “Dr. K.V. Rao Research Award, 2020” Hyderabad, India. Paper entitled “Roles of Metadherin in Breast cancer Progression”.

9. Oral presentation at The International Chemical Biology Society (ICBS2019), CSIR- Indian Institute of Chemical Technology, Hyderabad, India (November 2 - 4, 2019).

 Top 5 papers among 18 research publications 

1. Neeli PK, et al., (2020) A novel metadherinΔ7 splice variant enhances triple-negative breast cancer aggressiveness by modulating mitochondrial function via NFĸB-SIRT3 axis. Oncogene 39(10):2088‐2102. IF- 9.8

2. Neeli PK., et al (2022). DOT1L regulates MTDH-mediated angiogenesis in triple-negative breast cancer: intermediacy of NF-κB-HIF1α axis. FEBS J. PMID: 36017623 IF- 6.0

3. Neeli P*, Chai D, & Li Y (2023). Comparison of DNA vaccines with AS03 as an adjuvant and an mRNA vaccine against SARS-CoV-2. iScience. IF- 6.1 

4. Karnewar S, Neeli PK, Panuganti D, et al. (2018) Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: Relevance in age-associated vascular dysfunction. Biochim Biophys Acta Mol Basis Dis. 1864(4 Pt A):1115‐1128.

5. Shaikh A, Neeli PK, Singuru G, Kotamraju S (2021). A functional and self-assembling octyl-phosphonium-tagged esculetin as an effective siRNA delivery agent. Chem Commun (Camb). 57(92):12329-12332 IF: 6.8

Postdoctoral Associate, Department of Medicine, Baylor College of Medicine, Houston, TX, 12/14/2020- Present,

Doctoral research fellow, Department of Applied Biology, CSIR-IICT, India, 08/1/2015 to 07/31/2020,

Project fellow, CSIR-CCMB, Telangana, India, 05/22/2013 to 08/28/2014,

Project fellow, Osmania University, Telangana, India, 11/2012 to 04/2013,

Editorial board member, Frontiers in Oncology, 2022- Present,

Editorial board member, Journal of Immunology, 2022- Present,

Editorial board member, Science Discovery, 2022- Present,

Editorial board member, Cell Biology, 2022- Present,

Ad hoc reviewer (>30 Journals): I have been actively involved in the peer-reviewing of research and review papers for top tire journals, including The Drug Resistance Updates, Drug Discovery Today, BBA reviews on cancer, BBA Mol bas dis., Frontiers in Immunology, Vaccines, cancers, IJMS (MDPI), translational oncology, Experimental cell research, etc.,

Topical advisory committee member: Vaccines, IJMS (MDPI)

• Identification of oncogenes in TNBCs and developing targeted therapies for breast and prostate cancer, Throughout my doctoral studies at IICT, I investigated to uncover the mechanisms behind the metastatic nature of Triple-negative breast cancers (TNBCs). I identified genes responsible for the aggressive nature of TNBCs. I revealed MTDH as a key player driving the aggressive nature of TNBCs. I discovered a novel isoform of MTDH (MTDHΔ7) specific to TNBCs, which added MDTH as a new potential target for intervention. I have validated these findings in mouse models and patient samples, strengthening their clinical relevance (Neeli PK et al., 2020). Additionally, my investigation on the MTDH-DOT1L axis opens up a new possibility of therapeutic intervention. Targeting the DOT1L-MTDH axis could provide a novel approach in managing TNBC (Neeli PK et al., 2022). I found that the AMPK-activating compounds AICAR and Metformin inhibit the growth of TNBCs by decreasing MTDH levels (Gollavilli et al., 2015). Our group has focused on developing mitochondrial-targeted anti-cancer drugs for over a decade. By collaborating with potential chemists, we developed natural compounds (Glycyrrhetinic Acid) analogs that specifically target TNBCs in vitro and in vivo and studied their mechanism of action. (Kallepu S et al., 2020). My work on multidrug resistance proteins led to the discovery of ABCG4's role in doxorubicin efflux in prostate cancers (Mallappa S et al., 2019). my innovative strategy of combining doxorubicin with simvastatin to reduce cardiotoxicity while maintaining the efficacy in treating prostate cancers is a practical solution to a common clinical challenge. Overall, I used a multidisciplinary approach to understand and combat cancer. My findings can potentially transform treatment options and improve the lives of cancer patients.
• Identification of AMPK activators as anti-cancer and anti-atherosclerotic agents, During PhD, I have explored the role of AMPK-activators as anti-cancer therapeutic drugs. Esculetin, a natural compound derivative of Coumarin, has attracted much attention because of its wider pharmacological activities. However, it has a poor bioavailability in vivo, and do not work effectively against cancers. So we developed a novel esculetin called Mito-Esc by conjugating with a TPP cation, which showed a significant accumulation in mitochondria in TNBC cells. Mito-Esc induced ROS generation, a drop in Δψm (mitochondrial membrane potential), induced cell-cycle arrest leading to apoptotic cell death, there by suggesting that, oxidative stress at least, in part plays a role in Mito-Esc mediated cancer cell death. I continued my research on the Mito-Esc and found that Mito-Esc can act as a novel self-assembling small molecule siRNA delivery vector, while it can induce selective breast cancer cell death. The amphipathic nature of Mito-Esc delivers therapeutic siRNAs intracellularly without the need for any excipient to exacerbate the anti-proliferative effects (Shaikh A et al., 2021). Next, I investigated the efficacy of AMPK activators Metformin and Mito-esc in the mitigation of atherosclerosis in the setting of aging in Apoe-/- mice models. A chronic low-dose administration of Mito-Esc or Metformin greatly prevented alterations in lipid profile, blood pressure and atherosclerotic plaque formation in the setting of aging. They reduced the vascular senescence and pro-inflammatory cytokine levels and prevented the stress-related premature senescence in endothelial cells. They also improved the mitochondrial function. Overall, Mito-Esc or Metformin alleviated atherosclerosis in the setting of aging by delaying vascular senescence and pro-inflammatory processes, and by improving mitochondrial biogenesis and function (Karnewar S et al., 2018 and 2022).
• Discovered the novel antibodies, AI-based small molecule drugs targeting the mutant p53, Wild-type p53 is a tumor suppressor that inhibits tumor development via multiple pathways. Mutations in the p53 gene occur in approximately 50% of the human cancers. Mutant p53 results in the acquisition of gain-of-function to promote tumor progression. Therapeutic strategies have been developed to target mutant p53 including small compounds CRISPR/Cas9, small peptides. These therapeutic effects are unsatisfactory in the clinic, currently there are no effective drugs to mutp53 to address unmet clinical needs. We have developed a mAb against the R175H of human mut-p53 with a high level of specificity and no cross reactivity to WT p53. We confirmed the therapeutic effects in in vivo. We then designed a T-cell targeting bispecific antibody BsAb with dual specificity to p53-R175H antigen and mouse CD3 complex. Administration of the R175H-BsAb inhibited the tumor growth when combined with a PD-1 antibody treatment (D. Chai at al., 2023). The p53-Y220C mutations one of the common mutation that play a major role in cancer progression. We have applied artificial intelligence (AI)- powered virtual screening to identify small molecule compounds that can restore the wild-type p53 confirmation from p53-Y220C. From 10 million compounds AI screened a diverse set of 83 high-scoring hits against p53Y220C. We identified a small molecule, with a code name H3 that preferably target only p53Y220C mutation. H3 selectively reactivated p53-Y220C, rescued its transcriptional activity, and inhibited tumor development in mice models (Shan Zhou et al., 2023). I was involved in a meta-analysis screening of p53 antibodies in serum samples to correlate with survival outcome of cancer patients (Sobhani N et al., 2021).
• Developing novel DNA vaccines for infectious diseases including Covid-19, DNA vaccination is a smart and promising approach for treating infectious diseases and cancer as they are inexpensive, easy to manufacture, store, and transport. However, DNA vaccines have poor immunogenicity. We have improved the immunogenicity and efficacy of DNA vaccines by optimizing the prime-boost strategies, improved adjuvants, and advanced plasmid vectors. We developed a Spike-DNA vaccine that shows comparable immunogenicity with a leading mRNA vaccine (Moderna). We are the first ones to compare the DNA vaccine's efficacy in parallel with mRNA vaccines (Neeli P et al., 2023). Next, we applied the DNA vaccination strategy to develop vaccines against Hepatocellular cancers (HCC) that express mutant epitopes. Our HMGB1/GPC3 dual targeting DNA vaccine elicited a potential therapeutic effect in HCC (Xiaoqing Shi et al., 2023). In addition, we developed an adenovirus-based immune checkpoint vaccine that elicited a potent anti-tumor effect in renal carcinoma (Nan Jiang et al., 2023). Together, our DNA vaccine and adenoviral vaccine delivery approach produced a new and powerful anti-tumor efficacy to combat cancer and other infectious diseases.
• Developing novel CAR-T therapies and Immunotherapies and for multiple cancers, Multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and NK/T cell neoplasms are major causes of blood cancer morbidity and mortality. CD38 is a glycoprotein highly expressed on the surface of plasma cells and MM cells. We developed CAR-T cells that target specifically the cancer cells that are expressing CD38 on their surface and thus act as anti-cancer therapies. We demonstrated that CD-38 CAR-T cells work as the best anti-cancer therapy in combination with all-trans retinoic acid (ATRA). This technique has a translational value as the incorporation of the ATRA in CD-38 immunotherapies can be applied to treat a broad spectrum of lymphoid malignancies (Xu W et al., 2022). Currently we are working to develop DNA-based prophylactic and therapeutic cancer vaccines for multiple cancer types. We hope we can develop effective cancer vaccines with optimized vaccine scheduling, improved immunogenicity, and effective delivery systems.

baylor College of Medicine