BAY AREA & ANDERSON TEAM AGAINST ACQUIRED RESISTANCE - U54 PROGRAM (BAATAAR-UP)

Project Summary/Abstract: The goal of this BAATAAR-UP renewal program application within the NCI ARTNet
is to characterize the mechanisms of, and therapeutically counteract, acquired resistance to molecular therapies
in non-small cell lung cancer (NSCLC) by delineating the tumor-tumor microenvironment (TME) ecosystem and
its plasticity during treatment. Acquired resistance is defined as tumor progression that occurs during therapy
and after an initial tumor response. The overarching hypothesis is that acquired resistance to molecular therapies
can be thwarted by defining and exploiting vulnerabilities in the cellular, signaling, and geographic tumor
ecosystem networks that allow tumors to survive and grow during therapy. In lung cancer and other cancer types,
the use of targeted therapies that inhibit important and common oncogenic driver alterations such as mutant
EGFR and KRAS (G12C) and block immunosuppressive checkpoints such as PD1/PDL1 is improving patient
outcomes. A major challenge to transforming cancers into chronic or curable diseases is acquired resistance,
which enables lethal cancer progression in patients. Understanding the mechanisms underlying acquired
resistance is essential to develop counteracting strategies that improve patient survival. During the prior NCI
U54 DRSC funding period, our team uncovered several mechanisms of acquired resistance to targeted therapy
in human NSCLC by studying clinical specimens and innovative patient-derived models including humanized
murine models bearing patient-derived xenografts (PDXs) and patient-derived organoids (PDOs) with an intact
TME. Our expert team proposes to investigate these mechanisms, and identify others, synergistically and
iteratively via 3 Research Projects and optimal interactions with 2 Cores. A Data Science Core will analyze,
harmonize, centralize, and share data obtained across the basic and translational continuum using innovative
methods. An Administrative Core will ensure optimal project integration and internal and external interactions
with the ARTNet Consortium, and scientific and lay communities. Project 1 (Clinical tumor-TME acquired
resistance) is translational and uses clinical specimens and patient-derived models to test the hypothesis that
tumor macrophages and tumor fibroblasts promote acquired resistance via paracrine signaling interactions
including cytokine, CD47, and extracellular matrix (ECM) cues sensed by cancer cells and converging on survival
pathways such as YAP and NF-kB. Project 2 (PDX tumor-TME acquired resistance) is translational and uses
humanized mouse models to test the hypothesis that an immune-suppressive TME and activation of macrophage
and fibroblast signaling circuits that support tumor cell survival via PDK1, YAP, and NF-kB signaling promote
acquired resistance. Project 3 (PDO tumor-TME acquired resistance) is basic and uses synthetic lethal and
proteomic profiling in PDOs with a TME to test the hypothesis that signaling interactions involving the ECM,
TROP2, and CD47 promote acquired resistance. Synergistic, iterative interactions to study these mechanisms
across projects and systems will yield robust, translatable treatment strategies to counteract acquired resistance.

Grant Number: 5U54CA224081-08
NIH Institute/Center: NIH
Principal Investigator: Trever Bivona