# Project 1: Systematic discovery of cell-intrinsic mechanisms of cancer drug resistance

> **NIH NIH U54** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $652,398

## Abstract

Project 1 – Project Summary
Despite tremendous advances in our understanding of cancer pathogenesis, the treatment of individual
patients with either conventional chemotherapy or targeted agents remains highly empiric. To date, precision
medicine efforts in oncology have focused primarily on genetic or epigenetic biomarkers within an individual
tumor. However, not all marker-based predictions guarantee patient response, as many are the result of
correlations from population-based studies. Approaches that utilize individual patient tumors specimens for ex
vivo drug susceptibility testing are similarly limited by the process of generating a cell line and subsequent
effects on drug sensitivity. Existing assays that measure cancer cell growth, such as ATP-based growth assays
(CellTiter-Glo), require extended culture and a large volume of tumor cells. This precludes their use for disease
monitoring in most patients with cancer. Furthermore, these bulk approaches are ill-suited for characterizing
therapeutic susceptibility within subpopulations. Thus, there is a pressing need for rapid and facile approaches
to characterize therapeutic sensitivity within individual tumor specimens that capture heterogeneity and can be
applied to very small specimens, including minimal residual disease. Project 1 leverages a unique suite of tools
to profile the intrinsic factors that inform the responses of individual cancer cells to therapeutic interventions.
We will ask to what extent paired phenotypic and transcriptomic measurements can identify pathways that
mediate cell autonomous resistance and highlight therapeutic approaches to overcome that resistance. Cancer
cells will be isolated from primary tumors or from patient-derived cell lines/xenografts of both leukemias (as a
liquid tumor model) and colon/pancreatic cancers (as a solid tumor model). In contrast to Project 2, cells will be
measured in isolation without mimicking aspects of the microenvironment. Over a period of many hours, we will
examine distinct phenotypic attributes of the cells (mass and mass accumulation rate) and link these attributes
to the transcriptome at the single-cell level. We will then determine cell intrinsic mechanisms for resistance by
analyzing transcriptomic features of responding and non-responding tumor cells.

## Key facts

- **NIH application ID:** 10162308
- **Project number:** 5U54CA217377-05
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** SCOTT R MANALIS
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $652,398
- **Award type:** 5
- **Project period:** 2017-06-07 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162308

## Citation

> US National Institutes of Health, RePORTER application 10162308, Project 1: Systematic discovery of cell-intrinsic mechanisms of cancer drug resistance (5U54CA217377-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10162308. Licensed CC0.

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