# UCSF Project 1

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $524,054

## Abstract

PROJECT SUMMARY
 The discovery of specific molecular drivers of oncogenesis has led to a shift in the treatment of cancer
patients, with a move away from the use of conventional cytotoxic chemotherapy and towards molecularly
targeted agents that are often more effective and less toxic (e.g. EGFR and ALK inhibitors and immune-
checkpoint inhibitor immunotherapies). However, this success of targeted inhibitors and immunotherapy has
highlighted the challenge and importance of drug resistance. While patients often benefit from an initial and
profound response to these current treatments, the vast majority of responses are incomplete and result in a
residual disease state that serves as a prelude to subsequent tumor progression (acquired resistance). While
several studies have delineated mechanisms of acquired resistance to treatment with various targeted
inhibitors and immunotherapy, very little is known about the mechanisms underlying incomplete response and
residual disease during initial treatment. This is a critical knowledge gap to fill to understand the longitudinal
trajectories cancer cells take during treatment to form a drug-resistant tumor that leads to the clinical demise of
patients.
 In Project 1, we will dissect the basis of incomplete response and resistance to targeted therapy and
identify new treatment strategies to neutralize or eliminate residual disease and forestall resistance. We
propose to do so through the prism of lung cancer, the foremost cause of cancer mortality worldwide and a
paradigm-defining malignancy that illustrates both the successes and challenges of targeted therapy (and
immunotherapy). A unique and transformative feature of our project is the ability to capture clinical specimens
that include both liquid and tumor biopsies longitudinally from patients treated with targeted therapy (and
immunotherapy), both early following treatment initiation and at maximal radiographic tumor response (residual
disease). Coupled with our expertise in innovative methodologies such as tumor molecular profiling, genetic
and pharmacologic screens, and organoid and patient-derived xenograft modeling, this capability to capture
clinical samples from patients with residual disease affords an unprecedented window into the evolution of
response and resistance in patients that can be leveraged to therapeutically target the residual disease state to
enhance the magnitude and duration of response in patients. We will complement discovery efforts with the
focused analysis of candidate modulators of residual disease that we have already uncovered. We propose 2
Specific Aims to characterize and therapeutically suppress residual disease during targeted therapy in NSCLC:
Aim 1 will define the molecular portrait and identify therapeutic targets in targeted therapy residual disease in
oncogene-driven non-small cell lung cancer (NSCLC). Aim 2 will functionally test the impact of target
engagement to eliminate residual disease in oncogene-driven NSC...

## Key facts

- **NIH application ID:** 10241309
- **Project number:** 5U54CA224081-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Trever G Bivona
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $524,054
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241309

## Citation

> US National Institutes of Health, RePORTER application 10241309, UCSF Project 1 (5U54CA224081-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10241309. Licensed CC0.

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