ECM signaling as a druggable target for tumor therapy Rolf A. Brekken, PhD Rock Star Science for Nucleating Newcos Texas FreshAIR 2014 Venture Forum October 24, 2014

Scientific Concept  Tumors develop and progress in the context of the ECM  Tumor cells use the ECM as a survival signal and as a signal that drives progression  Collagen is an abundant protein in the ECM of tumors – decreases the efficacy of chemotherapy – drives tumor progression – Signals through DDRs

Scientific Concept  Fibrillar collagens (e.g., collagen I) bind to discoidin domain receptors (DDRs)  DDRs are RTKs implicated in cell survival, proliferation and migration  DDR1, typically expressed by epithelial cells, is the focus of the project.  DDRs are expressed broadly and bind GVMGFO collagen sequence  Coincident with DDRs and collagen deposition is the expression of SPARC  SPARC binds to GVMGFO on fibrillar collagens

Scientific Concept  SPARC and DDR1 compete for collagen  Absence of SPARC correlates with increased DDR1 activation and worse survival Von Hoff, et al 2011 LSL-Kras G12D : Ink4aArf lox/lox : p48 Cre/+ Suggests that DDR1 is a therapeutic target

Business Proposition  Targeted inhibition of collagen-induced DDR1 activity in tumor cells with a novel small molecule:7rh – Ready for lead optimization – Target tumors with high collagen, low SPARC and active DDR1 signaling

Major Indication  Stromal rich tumors – GI, breast are primary indications  Preclinical work has been done in models of pancreatic cancer – Stromal rich – chemoresistant  Expectation is that DDR1 inhibition will be applicable to multiple tumor types – Collagen is expressed broadly in various cancers

Patent Status  Provisional patents have been filed by UTSW

Key Data – primary project  Targeted inhibition of collagen signaling 7rh blocks collagen-DDR1 interaction and reduces DDR1 signaling

7rh Enhances Sensitivity to Gemcitabine ASPC-1PANC-1 Key Data – primary project

 Targeted inhibition of collagen signaling Blockade of collagen signaling enhances the efficacy of chemotherapy in orthotopic pancreatic tumors Active DDR1 Active PEAK1 Control 7rh WT mice SPARC -/- mice Toxicity None detected at therapeutic dosing levels with 7rh as a single agent or in combo with chemo 7rh

People  Collagen signaling – Kristina Aguilera, Brekken lab UTSW – Ke Ding, PhD, GIBH  Tuevol Therapeutics – David Foster,