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ECM signaling as a druggable target for tumor therapy
Rolf A. Brekken, PhD
Rock Star Science for Nucleating NewcosTexas FreshAIR 2014 Venture Forum
October 24, 2014
Scientific ConceptTumors develop and progress in the context of the ECMTumor 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-KrasG12D : Ink4aArf lox/lox : p48Cre/+
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 IndicationStromal rich tumors – GI, breast are primary
indicationsPreclinical 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 projectTargeted inhibition of collagen signaling
7rh blocks collagen-DDR1 interaction and reduces DDR1 signaling
7rh Enhances Sensitivity to GemcitabineASPC-1 PANC-1
7rh (nM) Avg IC50s
Gemcitabine (nM)Avg IC50s
500 nM 7rh + GemAvg IC50s
ASPC-1 368 (4) > 2000 (3) 35 (2)
PANC-1 497 (6) > 2000 (4) 211 (3)
Key Data – primary project
Key Data – primary projectTargeted inhibition of collagen signaling
Blockade of collagen signaling enhances the efficacy of chemotherapy in orthotopic pancreatic tumors
Active DDR1
Active PEAK1
Cont
rol
Cont
rol
7rh
WT m
iceSPARC
-/- 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, [email protected]
