# Project 4: Targeting genomic instability and evolution in myeloma

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2024 · $240,658

## Abstract

Project Summary – Project 4 Dana-Farber Cancer Institute
A prominent feature of multiple myeloma (MM) and other malignancies is significant genomic instability leading
to clonal evolution and disease progression. We have previously described the mutational landscape in multiple
myeloma (MM) and shown that the number of mutations correlates with overall and event free survival in MM. In
the current funding period, using deep WGS, we investigated 183 newly diagnosed patients with MM and
demonstrated a significant variability in mutational load in MM. Moreover, all MM subgroups had activated
mutational signatures indicative of homologous recombination (HR) and NER dysfunction as a prominent late
mutational process, whereas APOBEC signature is activated in the intermediate phase of disease progression
in high-risk MM. Importantly, a subgroup with low DNA damage had a superior outcome. Our recent studies also
demonstrate the acquisition of significantly higher number of mutations at relapse following high-dose therapy
compared to RVD (a 3-drug standard-dose combination) and identify HR dysfunction as a prominent underlying
mechanism. These observations are also consistent with our previous data which show that HR is dysregulated
and significantly contributes to genomic instability and development of drug resistance in MM. Investigating the
mechanisms underlying genomic evolution, we have also identified a kinase gene signature impacting DNA
repair (especially HR) and genome stability in cancer cells including MM. We further demonstrate that PDZ
Binding Kinase (PBK), a member of this signature, impacts DNA repair and genome stability in MM cells through
direct phosphorylation of DNA repair genes and that of a transcription factor FOXM1, which regulates major DNA
repair pathways. Based on these and other data, we hypothesize that MM genome is defined by complex clonal
architecture that drives the disease at diagnosis and evolves further at relapse and it is mediated by dysregulated
DNA repair and related genes. Towards this goal, we will investigate myeloma cell clonal complexity at diagnosis
and relapse and their impact on outcome (Specific Aim 1); functionally validate PDZ Binding Kinase (PBK) for
its impact on MM cell clonal evolution, growth and survival (Specific Aim 2); and evaluate PBK inhibitors, alone
and in combination with existing MM drugs, in vitro and in murine models of MM (Specific Aim 3). This study
will improve our understanding of mechanisms which contribute to genetic instability, clonal evolution and
progression in MM and will identify novel targets and therapeutic strategies to inhibit growth and prevent/delay
evolution of the disease.

## Key facts

- **NIH application ID:** 10894596
- **Project number:** 5P01CA155258-12
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Nikhil C. Munshi
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $240,658
- **Award type:** 5
- **Project period:** 2011-12-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894596

## Citation

> US National Institutes of Health, RePORTER application 10894596, Project 4: Targeting genomic instability and evolution in myeloma (5P01CA155258-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10894596. Licensed CC0.

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