Program Official

Principal Investigator

Mokenge P
Awardee Organization

H. Lee Moffitt Cancer Ctr & Res Inst
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Eligible
Project End Date

Novel Therapy to Inhibit IPMN Progression

Pancreatic ductal adenocarcinoma (PDA) is an incalcitrant malignancy with a 5-year survival of only 10%. Therefore, targeting PDA precursors is an area of the highest priority. Amongst the most prevalent and easily identifiable high-risk individuals with PDA precursors are patients with intraductal papillary mucinous neoplasm (IPMN). Currently, patients with IPMN are managed with active surveillance (AS) and surgery to develop highrisk stigmata. FDA-approved non-operative treatment of IPMN to prevent progression to PDA does not exist. Challenges to developing an effective IPMN agent include identifying agents that can be tested in human clinical trials, availability of an appropriate group of high-risk patients that can be entered into a clinical prevention trial, and identifying potential biomarkers that could predict the efficacy of chemoprevention agents. Recent work from our team has identified δ-tocotrienol (DT3) as a novel apoptosis-inducing agent for IPMN, MUC4 as a driver as well as a predictive biomarker of IPMN progression, and an ideal cohort of motivated patients with IPMN on AS, that provides new opportunities to address each of these high-priority challenges. In a recently completed NCI-sponsored Phase I window-of-opportunity trial, we observed that DT3 is safe and significantly induces apoptosis in the neoplastic cells of patients with IPMN. Our preliminary studies also suggest that MUC4 expression is associated with response to DT3. Further, we observed that MUC4 expression in the background of oncogenic KRAS results in the development of IPMN in mouse pancreas. Thus, the overall hypothesis for this proposal is that DT3 will block IPMN progression by targeting pathways that are crucial for the initiation, maintenance, and progression of IPMN precursor lesions. This hypothesis will be tested in two aims: In Aim 1, we will conduct a Phase II multi-institutional, randomized, placebo-controlled trial of DT3 in the prevention of IPMN progression (106 patients/arm) utilizing individuals from Moffitt Cancer Center, University of Nebraska Medical Center, and Mayo Clinic. The primary endpoint will be IPMN Progression-Free Survival based on international guidelines criteria after three years. Patients will be monitored with MRI/MRCP and endoscopic ultrasound-based on a standard of care. Further, correlative studies will utilize radiomics and tissue and serum samples to study the biomarkers of response and discern the mechanism of action of DT3. In Aim 2, we will define the molecular targets of DT3, the mechanism of biochemical responses, and identify biomarkers of DT3 in the genetically engineered model of IPMN (KCMUC4 Tg) that harbors the mutational combination of oncogenic KRAS and inducible MUC4 overexpression. Insights gained from the studies in Aim 2 will be validated with biospecimens obtained from patients in Aim 1. This multidisciplinary proposal will allow opportunities to reduce PDA mortality by advancing a promising noninvasive paradigm for reducing the risk of IPMN progression to PDA and providing novel insights into the molecular mechanisms contributing to the pro-apoptotic effects of DT3.


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  • Nallasamy P, Nimmakayala RK, Parte S, Are AC, Batra SK, Ponnusamy MP. Tumor microenvironment enriches the stemness features: the architectural event of therapy resistance and metastasis. Molecular cancer. 2022 Dec 22;21(1):225. PMID: 36550571
  • Lakshmanan I, Marimuthu S, Chaudhary S, Seshacharyulu P, Rachagani S, Muniyan S, Chirravuri-Venkata R, Atri P, Rauth S, Nimmakayala RK, Siddiqui JA, Gautam SK, Shah A, Natarajan G, Parte S, Bhyravbhatla N, Mallya K, Haridas D, Talmon GA, Smith LM, Kumar S, Ganti AK, Jain M, Ponnusamy MP, Batra SK. Muc16 depletion diminishes KRAS-induced tumorigenesis and metastasis by altering tumor microenvironment factors in pancreatic ductal adenocarcinoma. Oncogene. 2022 Nov;41(48):5147-5159. Epub 2022 Oct 21. PMID: 36271032
  • Raut P, Nimmakayala RK, Batra SK, Ponnusamy MP. Clinical and Molecular Attributes and Evaluation of Pancreatic Cystic Neoplasm. Biochimica et biophysica acta. Reviews on cancer. 2023 Jan;1878(1):188851. Epub 2022 Dec 16. PMID: 36535512
  • Zhang C, Atri P, Nallasamy P, Parte S, Rauth S, Nimmakayala RK, Marimuthu S, Chirravuri-Venkata R, Bhatia R, Halder S, Shah A, Cox JL, Smith L, Kumar S, Foster JM, Kukreja RC, Seshacharyulu P, Ponnusamy MP, Batra SK. Small molecule inhibitor against onco-mucins disrupts Src/FosL1 axis to enhance gemcitabine efficacy in pancreatic ductal adenocarcinoma. Cancer letters. 2022 Sep 19;551:215922. Epub 2022 Sep 19. PMID: 36285687
  • Bryant JM, Palm RF, Herrera R, Rubens M, Hoffe SE, Kim DW, Kaiser A, Ucar A, Fleming J, De Zarraga F, Hodul P, Aparo S, Asbun H, Malafa M, Jimenez R, Denbo J, Frakes JM, Chuong MD. Multi-Institutional Outcomes of Patients Aged 75 years and Older With Pancreatic Ductal Adenocarcinoma Treated With 5-Fraction Ablative Stereotactic Magnetic Resonance Image-Guided Adaptive Radiation Therapy (A-SMART). Cancer control : journal of the Moffitt Cancer Center. 2023 Jan-Dec;30:10732748221150228. PMID: 36598464
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  • Park MA, Zaw T, Yoder SJ, Gomez M, Genilo-Delgado M, Basinski T, Katende E, Dam A, Mok SRS, Monteiro A, Mohammadi A, Jeong DK, Jiang K, Centeno BA, Hodul P, Malafa M, Fleming J, Chen DT, Mo Q, Teer JK, Permuth JB. A pilot study to evaluate tissue- and plasma-based DNA driver mutations in a cohort of patients with pancreatic intraductal papillary mucinous neoplasms. G3 (Bethesda, Md.). 2023 Feb 9;13. (2). PMID: 36454217
  • Mehta R, Frakes J, Kim J, Nixon A, Liu Y, Howard L, Martinez Jimenez ME, Carballido E, Imanirad I, Sanchez J, Dessureault S, Xie H, Felder S, Sahin I, Hoffe S, Malafa M, Kim R. Phase I Study of Lenvatinib and Capecitabine with External Radiation Therapy in Locally Advanced Rectal Adenocarcinoma. The oncologist. 2022 Aug 5;27(8):621-e617. PMID: 35325225
  • Powers BD, Allenson K, Perone JA, Thompson Z, Boulware D, Denbo JW, Kim JK, Permuth JB, Pimiento J, Hodul PJ, Malafa MP, Kim DW, Fleming JB, Anaya DA. The impact of age and comorbidity on localized pancreatic cancer outcomes: A US retrospective cohort analysis with implications for surgical centralization. Surgery open science. 2023 Feb 11;12:14-21. doi: 10.1016/j.sopen.2023.02.001. eCollection 2023 Mar. PMID: 36879667
  • Permuth JB, Mesa T, Williams SL, Cardentey Y, Zhang D, Pawlak EA, Li J, Cameron ME, Ali KN, Jeong D, Yoder SJ, Chen DT, Trevino JG, Merchant N, Malafa M. A pilot study to troubleshoot quality control metrics when assessing circulating miRNA expression data reproducibility across study sites. Cancer biomarkers : section A of Disease markers. 2022;33(4):467-478. PMID: 35491771
  • Gardiner A, Kidd J, Elias MC, Young K, Mabey B, Taherian N, Cummings S, Malafa M, Rosenthal E, Permuth JB. Pancreatic Ductal Carcinoma Risk Associated With Hereditary Cancer-Risk Genes. Journal of the National Cancer Institute. 2022 Jul 11;114(7):996-1002. PMID: 35445726
  • Powers BD, McDonald J, Mhaskar R, Lee SJC, Permuth JB, Vadaparampil S, Gilbert SM, Denbo JW, Kim DW, Pimiento JM, Hodul PJ, Malafa MP, Anaya DA, Fleming JB. Hospital Surgical Volume Is Poorly Correlated With Delivery of Multimodal Treatment for Localized Pancreatic Cancer: A National Retrospective Cohort Study. Annals of surgery open : perspectives of surgical history, education, and clinical approaches. 2022 Aug 17;3(3):e197. doi: 10.1097/AS9.0000000000000197. eCollection 2022 Sep. PMID: 36199487
  • Kehrberg RJ, Bhyravbhatla N, Batra SK, Kumar S. Epigenetic regulation of cancer-associated fibroblast heterogeneity. Biochimica et biophysica acta. Reviews on cancer. 2023 May;1878(3):188901. Epub 2023 Apr 28. PMID: 37120098
  • Bhatia R, Siddiqui JA, Ganguly K, Thompson CM, Cannon A, Aithal A, Perumal N, Maurya SK, Li X, Cox JL, Gurumurthy CB, Rachagani S, Jain M, Nasser MW, Batra SK, Kumar S. Muc4 loss mitigates epidermal growth factor receptor activity essential for PDAC tumorigenesis. Oncogene. 2023 Mar;42(10):759-770. Epub 2023 Jan 9. PMID: 36624189
  • Ogunleye AO, Nimmakayala RK, Batra SK, Ponnusamy MP. Metabolic Rewiring and Stemness: A Critical Attribute of Pancreatic Cancer Progression. Stem cells (Dayton, Ohio). 2023 May 15;41(5):417-430. PMID: 36869789