Development of tumor targeting and stroma penetrating toxin for pancreatic cancer treatment

Abstract public domain (NIH RePORTER)

Project Summary Advanced pancreatic cancer is highly resistant to conventional therapeutic approaches. Low efficiency in drug delivery is a major clinical clinical challenge in the treatment of pancreatic cancer. The present of an extremely dense tumor stroma limits drug delivery into tumor tissues and hinders drug diffusion into tumor cells. Recent clinical success in cancer treatment using targeted protein therapeutic agants led the FDA approval of several antibody-drug conjugates (ADCs) and immunotoxins for targeted therapy hematological malignances and limited types of solid tumor. Depite of extensive efforts in the development of new ADCs and immunotoxin for preclinical studies and clinical trials, pancreatic cancer patients still showed a poor therapeutic response. Therefore, there is an urgent need for novel therapeutic agents capable of penetrating tumor stroma barrier, enhancing therapeutic responses in pancreatic cancer. To overcome stromal cellular and extracellular matrix barriers, we have developed a recombinant urokinase plasminogen activator receptor (uPAR) targeted ligand by fusing the amino terminal fragment (ATF) of uPA with the catalytic domain of matrix metalloproteinase-14 (ATFmmp14). Our results showed that ATFmmp14 is an excellent stroma-penetrating drig delivery ligand to increase intratumoral drug delivery and distribution into tumor cells, leading to enhanced therapeutic responses. The goal of this SBIR Phase 1 project is to develop and characterize uPAR targeted pseudomonas exotoxin (PE) with the ability of migration through dense tumoral stroma for effective delivery of modified PE38 or PE24 into cancer cells for targeted therapy of drug resisant pancreatic cancer. We hypothesize that ATFmmp14-PE toxin has a high efficiency of intratumoral delivery into pancreatic cancer and its stroma penetrating and uPAR receptor targeting abilities further facilitate PE toxin delivery into tumor cells to effectively induce cell death, leading to a strong therapeutic efficacy in drug resistant pancreatic cancer. In Aim 1 of the Phase 1 period, we will produce two types of ATFmmp14-PE fusion proteins, ATFmmp14-PE38KDEL (already produced and characterized) and ATFmmp14-PE24m (in progress), and optimize the expression and purification methods to obtain desired yield, purity, binding affinity, enzymatic activity, and cytotoxicity. We will then determine tumor targeting and stroma penetrating capabilities of ATFmmp14-PE38 and ATFmmp14-PE24m proteins in vitro and in a pancreatic cancer patient-derived xenograft (PDX) tumor model (Aim 2). Finally, we will evaluate systemic toxicity, immunogenicity and PK in normal mice and investigate , dose/schedule and therapeutic efficacy of ATFmmp14-PE38 and ATFmmp14/PE24m without or with in combination with nab-paclitaxel in a pancreatic cancer PDX model (Aim 3). Upon completion of this project, we will select a lead ATFmmp14-PE toxin for further translational development and submission of a phase II application aimed at the preclinical and IND enabling studies to bring this targeted therapy into a clinical trial in advance pancreatic cancer. Therefore, results of this SBIR sphase 1 research should have a significant impact on the development of a new combination therapy for overcoming therapy resistance in pancreatic cancer.

Public health relevance public domain (NIH RePORTER)

Project Narrative Advanced pancreatic cancer is highly resistant to conventional therapeutic approaches due to extremely dense tumor stroma limits drug delivery into tumor tissues and hinders drug diffusion into tumor cells. The goal of this SBIR Phase I project is to develop receptor targeted, stroma-penetrating therapeutic proteins with a strong activity in inducing cell death in tumor cells to overcome therapy resistance in pancratic cancer. The proposed research will develop two novel targeted, stroma penetrating toxin proteins and evaluate their target specificity and efficiency in intratumoral cell delivery of the toxin, systemic toxicity and therapeutic effect in a human pancreatic cancer patient derived tumor model in mice.