# Role of Oncogenic RAS in Multiple Myeloma Disease Progression

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2022 · $221,715

## Abstract

Project Summary/Abstract
 Despite improved therapies over the last 15 years, the plasma cell neoplasm multiple myeloma (MM)
remains incurable. The majority of patients ultimately relapse and succumb to drug-resistant disease. In MM,
the bulk of cancer cells lack the stem cell-like properties required for the maintenance of clonogenic growth
over time (i.e., self-renewal), and cells that have enhanced self-renewal will contribute to relapse and disease
progression. Therefore, targeting the cells responsible for self-renewal will lead to improved outcomes.
However, the development of stem cell directed therapies in MM is impeded by our current lack of
understanding in the molecular drivers and the phenotype of cells that are responsible for self-renewal. In
newly diagnosed MM, self-renewal and differentiation parallels normal B-cell hierarchy in that B-cell
progenitors, not differentiated plasma cells, display enhanced self-renewal potential. However, not all MM
tumors exhibit this hierarchal organization and we have shown that differentiated plasma cells from
relapsed/refractory MM also possess stem cell properties. We have also found that aberrant RAS pathway
activation, which is predominantly found in more differentiated plasma cells and associated with disease
progression, drives MM clonogenic growth, self-renewal, and proliferation. We hypothesize that the acquisition
oncogenic drivers, including mutant RAS, drive MM disease progression by conferring self-renewal in
differentiated progenitor compartments. Accordingly, we propose to: 1) Determine the role of oncogenic RAS
in MM disease progression in a murine model and 2) Determine the relationship between oncogenic RAS and
stem cell properties in MM patients. The expectation is that these studies will define the relationship between
disease stage, RAS mutations, phenotype, and stem cell functions and lead to better treatments for advanced
MM patients where there are currently few effective therapies.
 Dr. Gocke’s long-term goal is to become an independent laboratory physician-scientist that determines
the fundamental drivers of relapse and disease progression and translates these findings into potential
therapies for MM patients. Through this proposal Dr. Gocke will acquire the additional research skills and
career experience needed to reach this goal. In Aim 1, Dr. Gocke will learn how to perform clinically relevant
murine modeling of MM that can lead to a better understanding of disease evolution; and in Aim 2, he will
acquire the skills needed to utilize clinical specimens to determine the functional impact of genomic changes
and cellular phenotype on stem cell properties and response to targeted therapies. Acquiring these skills will
be critical to developing a relevant, impactful translational research program in MM.

## Key facts

- **NIH application ID:** 10401794
- **Project number:** 5K08CA218893-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Christian B Gocke
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $221,715
- **Award type:** 5
- **Project period:** 2018-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401794

## Citation

> US National Institutes of Health, RePORTER application 10401794, Role of Oncogenic RAS in Multiple Myeloma Disease Progression (5K08CA218893-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10401794. Licensed CC0.

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