# Project 4. Targeting genomic instability and evolution in myeloma

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2020 · $280,767

## Abstract

Project Summary (Project 4)
Genomic instability, which leads to genetic changes associated with progression of cancer to more aggressive
phenotypes and ultimately the development of resistance to therapy, is a prominent feature of multiple
myeloma (MM). Understanding genomic instability and its underlying mechanisms is, therefore, extremely
important to develop therapeutic strategies which would suppress clonal evolution and its impact on genomic
and clinical outcome. In previous funding period, we defined the mutational spectrum in MM at the time of initial
diagnosis and found heterogeneity across samples, with largely distinct sets of chromosomal rearrangements
and gene mutations present in individual patients. Importantly, serial sampling of patient MM cells revealed
diverse patterns of clonal evolution, including linear evolution, differential clonal response, or branching
evolution. We also identified at least two biologically distinct mutational signatures responsible for the majority
of observed mutations, suggesting a pattern of parallel, divergent, or even convergent evolution. Interestingly,
the number of mutations was the only factor correlating with overall as well as relapse free survival, thus
highlighting the importance of understanding the mechanisms of genomic instability in MM. The clonal
evolution which is probably driven by pressures from therapy, microenvironment, and inherent genomic and
epigenomic mechanisms, leads to both clonal selection and formation of new clones. By deep sequencing of
single gene IgH, we demonstrated that selection of very low frequency clone occurs following therapy, and that
new clones may come up due to ongoing mutational changes. Consistent with our previous data which
identified dysregulated homologous recombination (HR) as an important mechanism underlying genomic
evolution, we have observed that patients with increased HR activity had poor event-free survival compared to
the rest. We hypothesize that therapy affects both clonal selection and clonal evolution, driving the ultimate
tumor genotype and phenotype that eventually emerges at relapse, suggesting that targeting underlying
mechanisms of clonal evolution is necessary to achieve curative outcomes. To this end we will extend our
ongoing investigations to investigate the impact of therapy on genomic instability and associated clonal
selection, clonal evolution, and underlying mechanisms in MM (Sp Aim 1); identify mediators of genomic
instability in MM (Sp Aim 2); and assess the ability of inhibitors of genomic instability to impact evolution of
genomic changes in MM (Sp Aim 3). The proposed studies will further improve our understanding of genomic
instability and progression of MM, identify novel drugs, and may facilitate the development of therapeutic
strategies which would inhibit/reduce evolution and associated dismal outcome.

## Key facts

- **NIH application ID:** 9987301
- **Project number:** 5P01CA155258-09
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Nikhil C. Munshi
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $280,767
- **Award type:** 5
- **Project period:** 2011-12-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987301

## Citation

> US National Institutes of Health, RePORTER application 9987301, Project 4. Targeting genomic instability and evolution in myeloma (5P01CA155258-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987301. Licensed CC0.

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