Targeting Macrophages to Treat Soft Tissue Sarcomas

PROJECT SUMMARY
Soft tissues sarcomas (STS) is a broad term for multiple subtypes of cancer that start in soft tissues. Most STS
are treated in the same way in the clinic regardless of the subtype. STS encompasses over 50 histologic and
molecular subtypes, with each displaying variable clinical behavior. There is currently no unifying treatment
for STS subtypes beyond surgery, chemotherapy, and radiation.
Resolute Science Inc. is developing novel STS therapy by using TAMs to process and deliver anti-cancer agents
to solid tumors. Targeting TAMs to kill the associated cancer has the advantage of being tumor-agnostic
compared to that of targeting a specific cancer cell receptor. This approach bypasses concerns of tumor
heterogeneity and evolved resistance associated with therapeutics that target specific properties of each cancer
type. Our lead therapeutic, RS-5, is well-tolerated and demonstrated strong anti-cancer efficacy across multiple
murine sarcoma tumor models, including the subcutaneous (sc) and intracranial (ic) HT1080 sarcoma cell line
model and a doxorubicin-resistant patient derived xenograft (PDX) sarcoma model. Resolute’s modular drug
design allows for straightforward chemical substitutions of ligand, backbone, linker, and payloads. Finally, the
cost of commercial manufacturing will be significantly lower than that of antibodies and antibody-drug conjugates
(ADCs) which could significantly reduce the price of this cancer treatment for patients and insurers.
The overall goal of the Fast-Track program is to conduct studies that further show the efficacy of Resolute’s
platform molecule as therapy for different STS subtypes and perform pre-Investigational New Drug (IND) and
IND-enabling studies. Our Phase I goal for this SBIR Fast-Track proposal is to validate the choice of one subtype
of STS, Undifferentiated Pleomorphic Sarcoma (UPS) as an initial clinical indication for RS-5. The measure of
success to advance to Phase II is 1) establish dose response of RS-5 in a doxorubicin-resistant UPS model, 2)
establish anti-cancer efficacy equal or better than doxorubicin in a doxorubicin-naive PDX model, 3) demonstrate
anti-cancer efficacy in both male and female mice, 4) establish contribution of MTM to anti-cancer efficacy from
that of RS-5. In Phase II, we will perform pre-Investigational New Drug (IND) and IND-enabling studies with
potential expansion into other STS subtypes through additional efficacy studies. The measure of success for
Phase II is 1) demonstrate comparable or better anti-cancer efficacy of RS-5 at a well-tolerated dose to that of
doxorubicin at a well-tolerated dose in at least 1 additional PDX model, 2) the successful validation of bio-
analytical methods for nonclinical toxicology species and humans, and 3) conduct IND-enabling studies.
Completion of this Fast-Track proposal will result in validation of STS as our first clinical indication for RS-5 and
completion of the IND-enabling studies to support the clinical development of RS-5. Once completed, the Phase
I and II work will provide a rapid path for RS-5 to obtain approval for Phase I clinical testing.

Grant Number: 5R44CA285036-03
NIH Institute/Center: NIH
Principal Investigator: Faith Barnett