Developmental Research Program

Developmental Research Program

Director: David DeNardo, PhD

Program Application Information

The Pancreatic Cancer SPORE will fund up to three investigators per year in the Developmental Research Program. The 2025 deadline for applications is May 15, 2025.  The award will be $75,000 to $100,000 for one year beginning on August 1, 2025. Review the SPORE DRP Request for Proposals for more information.

SPORE DRP Overview

The goal of the SPORE in Pancreatic Cancer Developmental Research Program is to recruit and support developmental research projects in pancreatic cancer, for future incorporation as full SPORE projects or as the basis for applications for other major peer-reviewed funding. The types of research projects to be supported include basic research, clinical research, epidemiological studies, and cancer prevention and control in pancreatic cancer. Projects will expand the scope of translational research and increase the number of investigators committed to pancreatic cancer research. The Developmental Research Program is responsible for recruiting research projects that will promote pancreatic cancer research to help define the new treatment directions and to support early-stage pancreatic cancer research projects so that they may achieve independent funding through competitive applications including R01, SPORE, foundations and other mechanisms. This program is open to all of the institutions participating in the SPORE, and any of their collaborators to maximize the number of innovative and high-quality projects. In addition, plans call for development of new projects with other SPOREs. This program, along with the Career Enhancement Program, is consistent with the Siteman Cancer Center’s overall commitment to the recruitment of minority and underrepresented investigators. New research projects are solicited and funded through developmental funds. Two to three developmental projects will be funded each year throughout the life of the SPORE. Requests for Applications for developmental projects in pancreatic cancer research will be requested annually. All developmental project applications will be reviewed by a Research Development Advisory Committee consisting of scientists (representing basic and applied science) with expertise in pancreatic cancer, a biostatistician, a patient advocate and ad hoc members, as necessary (special expertise, no conflict of interest). This committee will make recommendations to the Pancreatic Cancer SPORE Steering Committee, which will make final funding decisions.

DRP Past Awardee’s

The DRP has funded a total of 10 projects to-date. Our DRP-funded investigators have  published their research in high-impact journals including Nature Medicine, Cancer Cell, and Nature Communications. Additionally research funded through the DRP has led to the development of multiple new clinical trials for patients with pancreatic cancer. A summary of our DRP awardees and their collaborative, high-impact work is provided below.

2016 Awardee

Scott Gerber, PhD

Revisiting neoadjuvant therapy for pancreatic cancer: Incorporation of new strategies. This project investigated whether radiation therapy augmented immune responses to pancreatic tumor in the neoadjuvant setting. The team developed a mouse model to test whether radiation therapy generated a locally potent immune response at the primary pancreatic tumor, and hypothesized that this neoadjuvant therapy would induce systemic antitumor immunity. Thus, this DRP aimed to determine whether neoadjuvant radiation therapy generated an antitumor immune response that reduced local recurrence/metastases in PDAC. The results of this study have been published in multiple top tier journals including Oncotarget, Radiation Research, Cell Reports, and Cancer Immunology Research.  Additional Gerber’s team has translated these findings to into the development of multiple planned Clinical Trials and additional grants from the National Cancer Institute, Wilmot Cancer Institute, and the University of Rochester Technology Development Award.

2016 Awardee

Christopher Maher, PhD

Understanding the role of long non-coding RNAs in pancreatic cancer. This project aimed to determine how primary tumors invade and metastasize secondary sites, with an overall goal of identifying novel targets and strategies to improve pancreatic cancer diagnostics and therapeutics. The results of this study were leveraged to obtain grants from the American Cancer Society and the National Cancer Institute.

 

2017 Awardee

Ryan Fields, MD

An autologous humanized mouse model to evaluate immune modulating therapeutics in pancreatic cancer. This proposal aimed to validate a recently described “MSTRG” HuMo model, which enables development of a human immune system encompassing both innate and adaptive cell populations, and apply this model to pancreatic adenocarcinoma. The results of Dr. Fields work have been published in the journals such as Oncotarget, Immunity, and Journal of Immunology.  Additionally, the results of this DRP award were leveraged to obtain additional awards from the National Cancer Institute and National Institutes of Health.

2017 Awardee

Julie Schwarz, MD PhD

Targeting the tumor stroma to improve neoadjuvant approaches in pancreatic cancer.

This project investigated why current chemoradiation strategies for pancreatic cancer are disappointingly ineffective in significant tumor regression. This is likely due to our poor understanding of how these therapies impact the fibrotic and immunologic components of the unique pancreatic cancer stroma. The project goal was to optimize the integration of stromal disrupting therapies to improve responses to radiation therapy in the neoadjuvant setting, and to integrate these therapies into a new clinical approach that will directly benefit pancreatic cancer patients. The exciting results of Schwarz’s study have been recently published in Science Translational Medicine with another paper accepted at Cancer Cell. Dr. Schwarz and team are in the final phases of developing a clinical trial based on the findings for patients at Siteman Cancer Center.

2017 Awardee

Aram Hezel, MD

Arid1a in pancreatic cancer: Transcription control therapeutic and clinical impact. This project investigated Arid1a gene mutation, which occurs in a significant number of pancreatic cancers. We created new models and systems to study this gene and the effects of its mutation in pancreatic cancers. These newly developed systems were used in this study to determine how cancers with Arid1a mutations can be more specifically and effectively treated. Data from this study was recently published in Gut, and a second manuscript is under review.

2018 Awardee

Delphine Chen, MD

Imaging PARP expression in pancreatic cancer. This project investigates poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), a promising new class of anticancer drugs. However, identifying patients who best respond to these drugs is challenging, especially because of side effects associated with PARPi therapy. Chen’s team developed a new positron emission tomography (PET) technique to image PARP expression in tumors. The goal of the project was to test whether this new PET technique could be used to identify patients who best respond to PARPi and spare non-responding patients from the side effects of ineffective treatment. Data from this study was leveraged to obtain additional funding from a Multi-PI Siteman Investment Program Award which is being used to support a clinical trial (NCT02469129) that is currently enrolling patients.

2018 Awardee

Yongjian Liu, PhD

PET imaging guided drug delivery for pancreatic adenocarcinoma therapy. This project developed an ultrasmall nanoparticle to improve chemotherapy drug delivery efficiency and treatment accuracy to pancreatic tumors. They investigated a targeted mechanism that used peptide binding to a CCR2 protein, which is highly expressed on monocytes/macrophages that are important components of the tumor microenvironment and a barrier for PDAC treatment. A radioactive copper-64 atom was incorporated into the nanoparticle to investigate whether it could serve as a platform for real-time PET imaging and efficient chemotherapy drug delivery to PDAC tumors. Data from this study was leveraged to obtain a National Cancer Institute grant and led to a clinical trial (NCT03851237) that is currently enrolling patients.

2018 Awardee

Adetunji Toriola, MD, PhD

Metformin use and pancreatic cancer survival in African Americans. This project investigated African American disparities in pancreatic cancer compared with other racial groups. Type II diabetes mellitus (DM) is one of the few modifiable factors that impacts pancreatic cancer survival. Notably, African Americans are approximately twice as likely as non-Hispanic Whites to have type II DM. Evidence is emerging that metformin (an anti-diabetic drug) is associated with better survival in pancreatic cancer patients. Metformin has been proposed as a useful adjunctive therapy for pancreatic cancer, although well-designed prospective studies investigating the associations of metformin use with pancreatic cancer survival are lacking. Thus, it is impossible to determine whether metformin will enhance the survival of African Americans with pancreatic cancer, further exacerbating the disparities. This project investigated associations between metformin use and duration of metformin use with survival and other clinical outcomes in African American pancreatic cancer patients with pre-existing type II DM. Toriola recently had a manuscript published in Cancer Epidemiology, Biomarkers & Prevention.

 

 

 

 

 

 

2019 Awardee

Mark Meacham, PhD

A novel high-throughput, ex vivo, vascularized tumor model for pancreatic cancer. This project leveraged an ex vivo, 3D microphysiological device created by their team of oncologists, cell biologists, immunologists, and biomedical engineers to study vascularized tumor biology. The current device consists of a central chamber in which fibroblasts (FB) and endothelial cells (EC) can form vasculature, and connected upper and lower chambers for tumor/non-tumor cells. Newly proposed model systems will recapitulate cancer biology, immunobiology, tumor-induced vasculature formation, and multiple aspects of the tumor microenvironment (TME) in a high-throughput format. The ability to precisely model the complex TME in vitro is crucial for the development of novel diagnostics and therapeutics. This project is developing a platform that recapitulates major features of the pancreatic cancer and robustly mimics human tumor biology and immunobiology for screening treatment combinations.

2019 Awardee

Kristen Bryant, PhD

Exploiting autophagy for pancreatic cancer treatment. This project builds on Bryant’s preliminary research, which demonstrated that pharmacological inhibition of the MAPK cascade promotes KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) addiction to autophagy; therefore, combining MEK-ERK and autophagy inhibitors could provide a new therapeutic strategy. This project aims to develop additional therapies to exploit the dependency of PDAC on autophagy

2020 Awardees

Linda Peterson, MD

Joseph Ippolito, MD PhD

Targeting pancreatic cancer with sodium glucose transporter 2 (SGLT2) inhibition. The goal of this project is to re-purpose sodium glucose cotransporter 2 inhibitors (SGLT2i) for the treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). SGLT2i are FDA-approved and are an appealing new, class of glucose-lowering therapies that have been shown to improve all-cause survival and decrease major cardiovascular events in patients with type 2 diabetes and in those with heart failure. Normally, SGLT2i block glucose re-uptake in the kidneys resulting in glucosuria that effectively lowers serum glucose. However, exciting new preclinical data show that there may be direct effects on PDAC tumors themselves, as: 1) functional SGLT2 is expressed in human PDAC tumors; 2) glucose uptake through SGLT2 plays a role in PDAC growth and survival in animals with human PDAC xenografts; and 3) treatment with the SGLT2i, dapagliflozin, significantly inhibits PDAC tumor growth and increases tumor necrosis. Thus, SGLT2i may be able to rob PDAC tumors of glucose necessary for growth and function. In addition, SGLT2i have other protective effects including inducing a mild ketonemia (which has anti-tumor effects) as well as reducing visceral obesity, which is associated with worse outcom0es in subsets of PDAC patients. Our primary hypothesis is that dapagliflozin is well-tolerated and safe to use in patients with metastatic PDAC. We also hypothesize that dapagliflozin will be efficacious as an adjunct to PDAC front-line chemotherapy assessed by decreased tumor markers mediated by its pleiotropic metabolic effects. To evaluate their hypothesis this project is conducting a phase Ib clinical trial of the SGLT2i, dapaglifilozin, added to standard of care front-line chemotherapy for metastatic PDAC patients.

2023 Awardees

Yongjian Liu, PhD
Kian-Huat Lim, MD, PhD

CCR2 targeted CuNCs-ECL1i-GEM is a novel cancer nanotheranostic. The outcome of patients with pancreatic ductal adenocarcinoma (PDAC) remains dire. To date, combination chemotherapy remains the mainstay treatment, but treatment response is neither universal nor durable. PDAC cells are intrinsically very resistant to chemotherapeutics. In addition, the extrinsic tumor microenvironment (TME) poses additional obstacles that stifle the effectiveness of therapies. Specifically, the abundance of myeloid-derived suppressor cells including inflammatory monocytes (IMs) and tumor-associated macrophages (TAMs) can further suppress the effect of chemotherapy and anti-tumor immunity. To simultaneously overcome these tumor-intrinsic and extrinsic barriers, we have now developed a novel therapeutic strategy through targeting the C-C motif chemokine ligand 2 (CCL2)/ C-C chemokine receptor type 2 (CCR2) axis, a well-established pro-tumorigenic signaling cascade in PDAC. Secretion of CCL2 by PDAC cells mobilizes CCR2-positive IMs from the bone marrow into the PDAC TME where they subsequently differentiate into immune-suppressive TAMs. Besides IMs, we found that CCR2 is also robustly expressed on the surface of PDAC cells, which can be exploited for selective therapeutic delivery into the PDAC cells using our platform. We have developed a novel nanotheranostic platform, CuNCs-ECL1i-GEM, in which a CCR2 binding peptide ECL1i is used for targeted delivery of chemotherapy gemcitabine (GEM). Through intrinsic radiolabeling of 64Cu, this renal clearable, in vivo degradable 64Cu-CuNCs-ECL1i-GEM could enable the noninvasive imaging using positron emission tomography (PET) to accurately target CCR2+ cells in the tumor of autochthonous PDAC mouse models for image-guided drug delivery. The CCR2 targeted and elevated delivery of GEM effectively depleted intratumoral TAMs, enriched CD8+ T cells and at the same time markedly reduced PDAC burden in the autochthonous KPC mice (p48-Cre; TP53flox/flox; KRASG12D). These changes set the stage for successful combination with checkpoint immunotherapy in eliminating PDAC burden and prolonged the survival of KPC mice. In a subcutaneous xenograft model using KRAS-INK4a tumor cells, 64Cu-CuNCs-ECL1i-GEM plus antiCTLA4 led to complete regression of large established tumors in immunocompetent mice. We submitted an RO1 based on these data and received a 37th percentile. However, we are confident that we can address the Reviewers’ comments with more experimental data, which we hope to gather through this grant, if funded. In this project, we hypothesize that CCR2 targeted CuNCs-ECL1i-GEM is a novel cancer nanotheranostic with robust immunomodulatory effect which will potentiate chemotherapy and checkpoint immunotherapy in PDAC.

2024 Awardee

Ben Major, PhD

Drugging NRF2 in Pancreatic Adenocarcinoma. Aberrant activation of the NRF2 oxidative/electrophilic stress response pathway is common in many cancer types where it promotes cellular resilience and tumor initiation, progression and therapeutic resistance. This project tests the hypothesis that pharmacological inhibition of the NRF2 transcription factor will suppress the growth of pancreas cancer, either as a monotherapy or as a combination agent with frontline chemotherapy. In pancreas cancer, the KRAS-Myc signaling axis, which is active in ~90% of tumors, promotes the expression and activity of NRF2. Genetic KO of NRF2 in KRAS mutant mouse models suppresses the formation and progression of pancreas cancer. Our team recently discovered a specific, potent and in vivo efficacious small molecule inhibitor of NRF2, setting the stage for this project. Using human and mouse pancreas cancer models, this project will determine if pharmacological inhibition of NRF2 will suppress PDAC progression and if it will increase the efficacy of standard-of-care FOLFIRINOX and gemcitabine plus nab-paclitaxel.

The NRF2 inhibitor is a game-changer for the cancer research community and possibly for cancer patients; the inhibitor is currently being tested in a phase 1 clinical trial. NRF2 is a proven and strong pro-tumorigenic factor in many cancers, increasing tumor initiation, tumor progression and driving resistance to chemotherapy, radiation therapy and immune check point inhibitors. The potential that NRF2 chemical inhibition will benefit PDAC cancer patients is high but has remained untested to date. The data we produce with this DRP pilot award will define the phenotypic and molecular impact of NRF2 inhibition on PDAC growth and chemoresponse.