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Updated: Dec 9, 2025
Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis
Published on: May 1, 2015
Mouse tumor susceptibility genes identify drug combinations for multiple myeloma
Shuling Zhang1, Wendy DuBois1, Ke Zhang1
1Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA.
Abstract:
Long-term genetic studies utilizing backcross and congenic strain analyses coupled with positional cloning strategies and functional studies identified Cdkn2a, Mtor, and Mndal as mouse plasmacytoma susceptibility/resistance genes. Tumor incidence data in congenic strains carrying the resistance alleles of Cdkn2a and Mtor led us to hypothesize that drug combinations affecting these pathways are likely to have an additive, if not synergistic effect in inhibiting tumor cell growth. Traditional and novel systems-level genomic approaches were used to assess combination activity, disease specificity, and clinical potential of a drug combination involving rapamycin/everolimus, an Mtor inhibitor, with entinostat, an histone deacetylase inhibitor. The combination synergistically repressed oncogenic MYC and activated the Cdkn2a tumor suppressor. The identification of MYC as a primary upstream regulator led to the identification of small molecule binders of the G-quadruplex structure that forms in the NHEIII region of the MYC promoter. These studies highlight the importance of identifying drug combinations which simultaneously upregulate tumor suppressors and downregulate oncogenes.
Insights
Researchers identified key genes in mouse plasmacytoma and found that combining an mTOR inhibitor with a histone deacetylase inhibitor synergistically suppressed tumor growth by targeting MYC. This highlights a strategy for developing new cancer therapies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Genetic studies identified Cdkn2a, Mtor, and Mndal as critical genes influencing plasmacytoma development in mice.
- Resistance alleles in Cdkn2a and Mtor suggested that targeting these pathways could inhibit tumor growth.
Purpose of the Study:
- To evaluate the synergistic potential of combining an mTOR inhibitor (rapamycin/everolimus) with a histone deacetylase inhibitor (entinostat).
- To assess the combination's activity, disease specificity, and clinical applicability in cancer therapy.
Main Methods:
- Utilized backcross, congenic strain analyses, and positional cloning to identify susceptibility/resistance genes.
- Employed systems-level genomic approaches to analyze drug combination effects.
- Investigated the impact of the drug combination on oncogenic MYC and tumor suppressor Cdkn2a.
Main Results:
- The combination of rapamycin/everolimus and entinostat demonstrated synergistic repression of oncogenic MYC.
- The drug combination also activated the Cdkn2a tumor suppressor.
- Identified MYC as a primary upstream regulator, leading to the discovery of small molecule binders for the MYC promoter G-quadruplex.
Conclusions:
- Simultaneously upregulating tumor suppressors and downregulating oncogenes is a crucial strategy for effective cancer therapy.
- Drug combinations targeting key genetic pathways offer promising therapeutic potential for inhibiting tumor cell growth.
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