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
LSL-KrasG12D : Ink4aArf lox/lox : p48Cre/+
Suggests that DDR1 is a therapeutic target
Von Hoff, et al 2011
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
Key Data – primary project
7rh Enhances Sensitivity to Gemcitabine
ASPC-1
PANC-1
7rh (nM)
Avg IC50s
Gemcitabine (nM)
Avg IC50s
500 nM 7rh + Gem
Avg IC50s
ASPC-1
368 (4)
> 2000 (3)
35 (2)
PANC-1
497 (6)
> 2000 (4)
211 (3)
Key Data – primary project
Targeted inhibition of collagen signaling
7rh
Control
SPARC-/- mice
7rh
WT mice
Control
Blockade of collagen signaling enhances the efficacy of chemotherapy in orthotopic
pancreatic tumors
Active
Active
PEAK1
DDR1
Toxicity
None detected
at therapeutic
dosing levels
with 7rh as a
single agent or
in combo with
chemo
People
 Collagen signaling
– Kristina Aguilera, Brekken lab UTSW
– Ke Ding, PhD, GIBH
Tuevol Therapeutics
– David Foster, David@tuevol.com