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Principal Investigator: Bassel El-Rayes
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2024
Award: $590,094
Funding agency: National Cancer Institute
SUMMARY/ABSTRACT
Cancer associated fibroblasts and pancreatic stellate cells (PSC/CAF) and abnormal tumor blood vessels are
two major factors that contribute to treatment failure. PSC/CAF contribute to the collagen-rich extracellular matrix
(ECM) which impairs drug delivery, promotes cancer cell survival and contributes to an immunosuppressive
environment. CAF have been shown to have a similar role in supporting metastatic sites of disease in
PDAC. Currently, no agent is available that can simultaneously selectively reduce activated PSC/CAF and
normalize angiogenesis. Both activated PSC/CAF and angiogenic endothelial cells selectively express high
levels of integrin v3. There is no expression of integrin v3 in normal tissue. We developed ProAgio, an
innovative protein drug with a distinct mechanism of action from currently available integrin-targeting agents in
targeting integrin v3 at a novel non-ligand binding site. ProAgio induces apoptosis of integrin v3
expressing PSC/CAF and angiogenic endothelial cells with a high efficiency by recruiting and activating
caspase-8 at the cytoplasmic domain of. Our preliminary data shows ProAgio has anti-tumor activity in
multiple PDAC models and enhances the effect of gemcitabine. Histologic analyses showed ProAgio decreased
collagen and depleted PSC/CAF in tumors. In a phase I clinical trial, single agent ProAgio has demonstrated
excellent safety profile, promising pharmacokinetic profile and anti-tumor activity in patients with PDAC.
We hypothesize that, by inducing apoptosis of integrin v3 expressing cells, ProAgio will specifically deplete
both angiogenic endothelial cells and activated PSC/CAF leading to inhibition of collagen deposition in PDAC
tumors, which will enhance drug delivery and increase the sensitivity of PDAC to established therapies. This
Project has three Specific Aims: 1) To characterize the toxicity and determine the recommended phase II dose
of ProAgio in combination with gemcitabine and nab-paclitaxel. We will conduct a phase I clinical trial of ProAgio
in metastatic PDAC patients with no prior therapy with gemcitabine and nab-paclitaxel. The goal is to determine
the recommended phase II dose, evaluate pharmacokinetics of ProAgio, and characterize toxicity. A secondary
objective is to obtain preliminary activity data (overall response rate) for ProAgio with gemcitabine and nab-
paclitaxel in PDAC. 2) To analyze the effect of ProAgio in patient tumors and validate the mechanism of drug
action. PDAC patients enrolled in the expansion phase will undergo paired pre- and post-treatment biopsies. We
will validate mechanism of ProAgio action by assessing changes in intratumoral collagen, blood vessels,
PSC/CAF subtypes, immune cells, and αvβ3 expression in these patient samples. Samples will be analyzed via
multiplex immunofluorescence with spatial quantification and single cell RNA sequencing. 3) To evaluate the
pharmacodynamics effects of ProAgio on angiogenesis and tumor perfusion. The perfusion changes in tumors
after treatment with ProAgio plus chemotherapy will be measured using quantitative DCE-MRI in all patients.
Terms: <Address><After Care><After-Treatment><Aftercare><Anzatax><Apoptosis-Related Cysteine Protease Gene Caspase 8><Apoptotic Cysteine Protease Gene><Apoptotic Protease MCH-5 Gene><Asotax><Binding><Binding Sites><Biology><Biopsy><Blood><Blood Reticuloendothelial System><Blood Vessel Tumor><Blood Vessels><Blood flow><Body Tissues><Bristaxol><Buffers><CAP4><CAP4 protease><CASP8><CASP8 Protein><CASP8 gene><Cancers><Caspase-8 Gene><Caspase-8/Flice><Cell Body><Cell Survival><Cell Viability><Cell-Extracellular Matrix><Cells><Clinical><Clinical Trials><Collagen><Combining Site><Common Rat Strains><Cytoplasmic Domain><Cytoplasmic Tail><Cytotoxin><Data><Data Set><Deposit><Deposition><Development><Difluorodeoxycytidine><Disease><Disorder><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drugs><ECM><Early-Stage Clinical Trials><Endothelial Cells><Enrollment><Environment><Extracellular Matrix><FADD-Homologous ICE/CED3-Like Protease Gene><FADD-Like ICE><FADD-Like ICE Gene><FADD-homologous ICE/CED3-Like Protease><FDA approved><FLICE><FLICE protein><Fibroblasts><GEM model><GEMM model><Genetically Engineered Mouse><Goals><Heterograft><Heterologous Transplantation><Histologic><Histologically><ICE-Like Apoptotic Protease 5 Gene><Immune><Immunes><Immunodeficient Mouse><Immunofluorescence><Immunofluorescence Immunologic><Impairment><Induction of Apoptosis><Integrin Inhibition><Integrin aVBeta3><Integrin alpha-v beta-3><Integrin alphaVbeta3><Integrin αVβ3><Integrins><Integrins Extracellular Matrix><KPC genetically-engineered mouse><KPC model><KPC mouse><KPC murine><Kinases><LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre><LSL-KrasG12D/+;LSL-p53R172H/+;Pdx-1-Cre><MACH protein><MACH-Alpha-1/2/3 Protein Gene><MACH-Beta-1/2/3/4 Protein Gene><MCH5><MCH5 Isoform Alpha Gene><MORT1-Associated CED-3 Homolog Gene><MORT1-Associated CED3 Homolog Gene><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Mch5 protease><Measurement><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Mice><Mice Mammals><Molecular Interaction><Monkeys><Murine><Mus><NMR Imaging><NMR Tomography><Neoplasms in Vascular Tissue><New Agents><Normal Tissue><Normal tissue morphology><Nuclear Magnetic Resonance Imaging><PDA model><PDAC Model><Paclitaxel><Paclitaxel (Taxol)><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Perfusion><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Phase><Phase 1 Clinical Trials><Phase 1b Trial><Phase I Clinical Trials><Phase I Study><Phase Ib Trial><Phosphotransferase Gene><Phosphotransferases><Praxel><Pre-Clinical Model><Preclinical Models><Prior Therapy><Protein Engineering><Proteins><Rat><Rats Mammals><Rattus><Reactive Site><Recommendation><Refractory><Resistance><Role><Safety><Sampling><Site><Stable Disease><Survival Rate><Taxol><Taxol A><Taxol Konzentrat><Therapeutic><Tissues><Toxic effect><Toxicities><Translating><Transphosphorylases><Treatment Failure><Treatment-related toxicity><Tumor Angiogenesis><Vascular Neoplasms><Vascular Tissue Tumor><Vascular Tumor><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><Zeugmatography><aVBeta3><alpha-v beta-3 Integrin Receptors><angiogenesis><anti-tumor agent><blood perfusion><blood vessel neoplasm><cancer cell><caspase-8><chemotherapy><contrast enhanced><dFdC><dFdCyd><developmental><drug action><drug/agent><enroll><extracellular><gemcitabine><genetic protein engineering><genetically engineered mouse model><genetically engineered murine model><image-based method><imaging method><imaging modality><improved><inhibitor><innovate><innovation><innovative><malignancy><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-invasive imaging><noninvasive imaging><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pancreatic stellate cell><participant enrollment><patient enrollment><patient oriented outcomes><phase 1 study><phase I protocol><post treatment><pre-clinical><preclinical><prevent><preventing><protein design><recruit><resistance to therapy><resistant><resistant to therapy><response><safety testing><scRNA-seq><selective expression><selectively expressed><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><targeted agent><therapeutic resistance><therapeutic toxicity><therapy associated toxicity><therapy failure><therapy related toxicity><therapy resistant><therapy toxicity><tool><treatment effect><treatment resistance><treatment toxicity><treatment-associated toxicity><tumor><vascular><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model>