The Lustgarten Foundation-AACR Career Development Award for Pancreatic Cancer Research, in Honor of John Robert Lewis, represents a joint effort to encourage and support early career scientists engaged in pancreatic cancer research who are members of racial or ethnic groups that have been shown to be underrepresented in the cancer-related sciences workforce. The Lustgarten Foundation-AACR Career Development Award for Pancreatic Cancer Research, in Honor of Ruth Bader Ginsburg, represents a joint effort to support the career advancement of a female scientist engaged in pancreatic cancer research.

2022 grantees

Research

The pro-tumorigenic activities of Heparan sulfate proteoglycans (HSPGs) are regulated by enzymatic modification of their heparan sulfate (HS) moieties. While mammalian heparanases promote extracellular matrix remodeling, invasion, and metastasis, bacterial heparinase depolymerizes HS through a contrasting mechanism, resulting in the suppression of tumor growth. However, the inability to restrict bacterial heparinase activity to tumor tissue has limited its use as a therapeutic agent. Using attenuated, tumor-targeting Salmonella typhimurium (ST) vectors, Dr. Manuel and his team have developed the first recombinant ST expressing functional heparinase through a tightly regulated, inducible promoter. The goal of their study is to determine the impact of this novel agent on nutrient scavenging and therapeutic resistance in models of pancreatic cancer.

Biography

Dr. Manuel earned his bachelor’s degree in Microbiology from San Diego State University and his PhD in Virology from Harvard. He is currently an Assistant Professor at the Beckman Research Institute of the City of Hope. The overall goal of his research program is to develop microbial-based therapies for the treatment of solid and hematological malignancies, i.e., “Bugs as Drugs”. His lab has been primarily focused on engineering recombinant, tumor-colonizing Salmonella to curtail processes contributing to therapeutic resistance in pancreatic cancer, namely desmoplasia and macropinocytosis.

Acknowledgment of Support

The Lustgarten Foundation-AACR Pancreatic Cancer Career Development Award, In Honor of John Robert Lewis, will allow me and my team to delve into key aspects of our microbialbased therapy. This is an important endorsement of our work and will ultimately have a significant impact on patients with advanced pancreatic cancer.

Research

Oncogenic KRAS (KRAS*) is the key driver of pancreatic ductal adenocarcinoma (PDAC) PDAC, maintaining tumor growth, and thereby, making it an ideal therapeutic target. However, both pre-clinical and clinical studies reveal adaptive resistance mechanisms in cancer to the treatment of KRAS* inhibitors (KRASi). Dr. Hou recently discovered that tumor-associated macrophages (TAMs) drive the KRAS* bypass by nourishing PDAC cells. In the project, Dr. Pingping Hou will explore the TAM subpopulation that promotes KRASi resistance in spontaneous PDAC mouse models and dissect the crosstalk of “pro-resistance” TAMs with tumor cells and cytotoxic T cells by various single-cell assays. The mechanistic insights gained can facilitate the development of novel combinatorial approaches with KRASi.

Biography

Dr. Hou received her PhD in cell biology from Peking University. After training in cancer biology as a postdoctoral fellow at the University of Texas MD Anderson Cancer Center, she joined the Center for Cell Signaling and the Department of Microbiology, Biochemistry and Molecular Genetics at Rutgers New Jersey Medical School. She is currently a tenure-track Assistant Professor at Rutgers New Jersey Medical School.

Acknowledgment of Support

With the support from the 2022 Lustgarten Foundation-AACR Pancreatic Cancer Career Development Award, In Honor of Ruth Bader Ginsburg, I am able to employ state-of-the-art single-cell technologies to comprehensively characterize the remodeling of tumor-associated macrophages and delineate the intercellular interactions that regulate pancreatic tumor response to KRAS inhibitors.

2021 grantees

Research
Pancreatic adenocarcinoma (PDAC) is a poorly immunogenic tumor characterized by low mutational burden and limited responses to immunotherapies. PDAC tumors, similar to other solid tumors, exhibit alterations of cellular glycosylation, including the abundant expression of the truncated O-glycan Tn antigen. Tn antigen is the ligand for the macrophage galactose-type lectin (MGL) expressed by tolerogenic antigen presenting cells and M2-phenotype macrophages. Using single-cell RNA sequencing of tumor immune infiltrate and bone marrow, Dr. Posey seeks to determine how the Tn antigen shapes the PDAC immune microenvironment as well as the systemic immune composition. In addition, he plans to adoptively transfer anti-Tn CAR-T cells to mice bearing heterogeneous Tn+ PDAC tumors to test whether disrupting the MGL-Tn axis will decrease the local immunosuppression within the tumor and improve anti-tumor responses in PDAC tumors.

Biography
Dr. Posey has BS degrees in biochemistry and bioinformatics from the University of Maryland, Baltimore County (UMBC), and a PhD in genetics from the University of Chicago. He completed postdoctoral training at the University of Pennsylvania, where he generated glycosylation-specific chimeric antigen receptors to precisely target tumor glycoforms of MUC1. He is currently an assistant professor in the Department of Systems Pharmacology and Translational Therapeutics at the University of Pennsylvania, a member of the Parker Institute for Cancer Immunotherapy, and a research health scientist at the Philadelphia Veterans Administration Medical Center.

Acknowledgment of Support
I am grateful to accept the Lustgarten Foundation-AACR Career Development Award for Pancreatic Cancer Research, in honor of John Robert Lewis. This award will support and expand my laboratory’s scientific enterprise. Importantly, we will investigate an underappreciated immune axis in pancreatic cancer and devise therapeutic strategies to eventually benefit patients.

Research
Dr. Engle has previously shown that aberrant glycan CA19-9 expression accelerated pancreatic tumor progression and increased metastatic dissemination in mice. In this work, she aims to elucidate the cell intrinsic and extrinsic roles of CA19-9 in pancreatic cancer metastasis. Using models of liver metastasis in monobiotic and parabiotic hosts, she and her team are set to identify the CA19-9 modified ligands that contribute to remodeling the local and distal microenvironment. In addition, they plan to characterize the signaling alterations that occur in the liver (the primary site of pancreatic cancer metastasis) in the presence of CA19-9 produced by the pancreas, using organoid co-culture approaches. Thirdly, they plan to assess the impact of abrogating the CA19-9 receptor E-selectin on metastatic dissemination and gene expression programs.

Biography
Dr. Engle received her BA in biological sciences and Asian & Middle Eastern studies from Northwestern University. She completed her doctorate in biology at the University of California, San Diego and the Salk Institute for Biological Studies. After completing her postdoctoral fellowship at the Cambridge Research Institute in England and Cold Spring Harbor Laboratory, she was recruited to start her own laboratory at the Salk Institute. Dr. Engle is also the recipient of an NCI Career Transition Award, the Theodore T. Puck Award, and other notable distinctions.

Acknowledgment of Support
Having lost close family members to pancreatic cancer, it has been my dream to start a dedicated pancreatic cancer research lab. The Lustgarten-AACR Career Development Award, in honor of Ruth Bader Ginsburg will enable me to harness my personal and scientific passion to make inroads against this devastating disease.