# Natural Products with Selective Cytoxicity to Non Small Cell Lung Cancer

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $608,607

## Abstract

This application aims to identify novel therapeutic vulnerabilities (drug targets or target pathways) that can
be exploited by natural product chemicals (NPs) in a panel of ~130 non-small cell lung cancer (NSCLC) cell
lines. Many of these cell lines were established from human tumors by the Minna laboratory (collaborator)
and recapitulate ~85% of the molecular features of their originating tumor. In addition, we aim to link these
selective vulnerabilities to biomarkers through the analysis of somatic mutations, gene expression,
proteomics and metabolomics data obtained at UTSW on the cell line panel. Furthermore, we will carry out
mechanism of action studies utilizing a method developed at UTSW, Functional Signature Ontology
(FUSION) to link gene expression profiles to a given mechanism of action. The platform will give
mechanism of action hypotheses that we can further investigate with detailed biochemical and cell biology
approaches. In initial screening of ~6,000 natural product fractions, we identified ~75 natural product
fractions, that kill subsets of the NSCLC cell lines but not immortalized human bronchial epithelial cell lines.
These will be the starting point for further studies.
Our goal in this proposal is to identify the active natural product from the ~75 natural product fractions that
have given unique signatures and to identify 1) a molecular target or pathway, 2) identify a putative
biomarker that predicts sensitivity to the natural product, 3) validate the selective toxicity in organoid and in
vivo models of lung cancer. Importantly, we have substantiated the utility of our unbiased, data-driven,
bioinformatics pipeline using data generated at UT Southwestern, and through other large efforts (TCGA,
COSMIC, etc.). For NSCLC, we have formulated therapeutic hypotheses of biomarker and perturbagen
relationships for all of the synthetic small molecules and natural product fractions we've screened.
!

## Key facts

- **NIH application ID:** 10126817
- **Project number:** 5R01CA225960-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JOHN B MACMILLAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $608,607
- **Award type:** 5
- **Project period:** 2018-04-19 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126817

## Citation

> US National Institutes of Health, RePORTER application 10126817, Natural Products with Selective Cytoxicity to Non Small Cell Lung Cancer (5R01CA225960-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10126817. Licensed CC0.

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