# Multi-dimensional targeted mass spectrometry technology for pathway-scale functional proteomics

> **NIH NIH R21** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $195,315

## Abstract

Project Summary
The advent of molecular biology and molecular profiling in clinical medicine has transformed our understanding
of the molecular basis of human cancer. As a result, we are increasingly improving the classification of human
tumors based on their specific genetic and molecular mechanisms of pathogenesis. However, currently only a
small number of mutant alleles guide treatment decisions, while most observed mutations remain of unknown
pathologic and clinical significance. In addition, even for recently approved drugs, such as those targeting
activated kinase signaling, clinical efficacy is highly varied, with no currently satisfactory means to identify
molecular markers of response and resistance. Quantitative measurements of the abundance of proteins and
stoichiometry of their regulatory post-translational modifications can be used to determine activation states of
of pathways and cells. However, current quantitative mass spectrometry techniques are limited by peptide ion
fragmentation, duty cycles that restrict assays to about 100 proteins, and limited scalability to permit high-
throughput clinical applications. To address this need, and broadly enable transformative future advances in
precision oncology and patient outcomes, we have recently developed a new method with 3 orders of
magnitude improvement in sensitivity, termed accumulated ion monitoring (AIM). Using AIM, we developed
the Quantitative Cancer Proteomics Atlas (QCPA) for functional profiling of biochemical processes mediating
aberrant survival of cancer cells. In principle, this technology permits highly multiplexed, quantitative analysis
of the expression and biochemical activity of thousands of proteins, covering most recurrently mutated and
known pathogenic pathways in cancer cells, and designed to be applied to clinically-accessible, microgram
patient specimens. The objective of this proposal is to develop scalable and high-throughput mass
spectrometry technology for proteome-wide and pathway-scale profiling of hundreds of clinical specimens on
the hours time scale. Our central hypothesis is that implementation of high-efficiency duty-cycle and ion
multiplexing quantitative proteomics will enable high-throughput functional molecular profiling for both basic
science and clinical applications. Aim 1 will develop pathway-scale functional mass spectrometry proteomic
mapping technology based on multiplex and triggered ion monitoring. Aim 2 will implement tandem mass
tagging for high-throughput quantitative mass spectrometry for scalable functional profiling of clinical cancer
specimens. Successful completion of this proposal is expected to close the technical gap currently preventing
the use of mass spectrometry for comprehensive functional profiling of clinical specimens. This research will
have broad significance because improved quantitative functional measures of cell signaling are needed to
overcome persistent challenges that limit progress in cancer biology and cl...

## Key facts

- **NIH application ID:** 9872139
- **Project number:** 5R21CA235285-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Alex Kentsis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,315
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872139

## Citation

> US National Institutes of Health, RePORTER application 9872139, Multi-dimensional targeted mass spectrometry technology for pathway-scale functional proteomics (5R21CA235285-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9872139. Licensed CC0.

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