Tumor-targeted delivery of radio/chemotherapy in pancreatic cancer.

Abstract public domain (NIH RePORTER)

Project Summary Tezcat Biosciences is developing novel receptor-independent intracellular drug delivery technology with a unique mechanism of action to treat the most recalcitrant cancers, such as mutant RAS pancreatic cancer. Pancreatic ductal adenocarcinoma cancer (PDAC) is associated with a dismal 5-year survival rate and pancreatic cancer patients today have virtually the same therapeutic options available to patients decades ago. This dearth of effective treatments is due in part to the notorious difficulty in targeting the genetic driver of PDAC, oncogenic RAS, as well as features of the PDAC tumor microenvironment itself which obstruct drug delivery. We have observed that mutant RAS PDAC cells display high levels of macropinocytosis, a nutrient scavenging process that facilitates the bulk engulfment of extracellular fluid and its solutes. Our drug candidate, TZT-102, utilizes our proprietary macropinocytosis-selective monobody that carries an FDA-approved cytotoxic payload (MMAE). Results from previous projects demonstrate that TZT-102 has robust anti-tumor activity in mutant RAS PDAC xenograft and orthotopic models without displaying systemic toxicity. As cancer cells, especially mutant RAS PDAC, exhibit high rates of acquired drug resistance, we are developing a novel dual-payload approach that combines the anti-microtubule payload (MMAE) with a DNA-damaging radioisotope. This proposal will utilize an imaging radioisotope (67Ga) to first provide proof-of-concept for 1) feasibility of synthesis and radiolabeling of the parent compound (TZT-102), and 2) biodistribution and tumor imaging data to confirm that the dual-payload conjugate maintains tumor-targeting capabilities. Tezcat has entered into a license agreement with NYU Langone Health for exclusive, worldwide rights to the technology being developed. Successful completion of the aims will support a Phase II SBIR application for testing of a dual-payload carrying a therapeutic radioisotope (177Lu).

Public health relevance public domain (NIH RePORTER)

Project Narrative: Tezcat Biosciences is an early-stage biotechnology company focused on developing innovative therapeutics to treat mutant RAS cancers. In this Phase I STTR, Tezcat is exploring the utility of a dual-payload protein-drug conjugate, combining a validated microtubule inhibitor and radionuclide, for the treatment of mutant RAS pancreatic cancer.