DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Genetic Analysis of TSC Tumors Identifies Novel Therapeutic Targets

Posted May 14, 2021

Krinio Giannikou, Ph.D., Brigham and Women’s Hospital
Mahsa Zarei, Ph.D., Texas A&M University

Dr. Krinio Giannikou
Dr. Krinio Giannikou
Dr. Mahsa Zarei
Dr. Mahsa Zarei

Tuberous sclerosis complex (TSC) is a genetically inherited disorder characterized by tumor development throughout the body. These tumors cause pathological disturbances by disrupting the normal function of the host tissue. TSC affects multiple organ systems including the brain, heart, kidneys, skin, and lungs. Kidney angiomyolipomas (AML) and lung lymphangioleiomyomatosis (LAM) are known to occur in TSC due to loss of function of the tumor suppressor genes, TSC1/TSC2, leading to tumor development. The role of additional epigenetic and transcriptional events, which may also drive AML/LAM development, are unknown. Recently, two researchers funded by the Tuberous Sclerosis Complex Research Program (TSCRP) investigated these genetic underpinnings of tumor development and potential treatments in TSC.

With support from a TSCRP Postdoctoral Development Award from fiscal year 2016, Dr.Krinio Giannikou at Brigham and Women’s Hospital explored the gene expression profile of AML/LAM tumors and performed targeted genetic analysis of TSC tumors in search of gene program active enhancer/super-enhancers and transcription factors that drive expression of multiple genes that may play a critical role in AML/LAM development and progression. Dr. Giannikou works closely with Dr. Mahsa Zarei at Texas A&M University, who is supported by funding from a fiscal year 2017 TSCRP Exploration –Hypothesis Development Award. Dr. Zarei is investigating the transcriptional and metabolic mechanisms that cause selective cell death of TSC-deficient cells with the long-term goal of identifying strategies that selectively kill TSC2-deficient cells, thereby decreasing the need for continuous anti-tumor therapy in TSC.

The researchers found that kidney AML/LAM tumors have a unique transcriptional profile that is dissimilar from other malignancies and normal tissues. They identified a set of candidate transcriptional driver genes that are highly expressed in AML in comparison to other cancers. Through innovative combinatorial genetic analysis techniques, the research team identified a set of novel transcription factors as super-enhancers, which are highly expressed in kidney AMLs, that might drive tumor growth. Dr. Giannikou writes, “We have used cutting-edge genomics approaches including RNA-Seq and ChIP-Seq in order to study renal AMLs and LAM tumors direct from TSC subjects in an unbiased genome-wide manner for [the] first time. Our studies have allowed us to understand better the chromatin state of these tumors and gave us the opportunity to define a set of the tissue/cell-specific active enhancers and super-enhancers that might contribute to tumor development and progression.” Overall, this work has identified unique genetic signatures for AML/LAM and several novel gene regulators that may be critical for kidney and/or lung tumor development, which could become novel therapeutic targets. The Zarei group has confirmed that targeting specific tumor cell essential genes will selectively induce cell death of TSC-null cells and that inhibition of transcription regulators is a promising therapeutic approach for treatment of TSC-associated tumors. These studies were performed in collaboration with other TSCRP-supported researchers including Drs. Elizabeth Henske, Heng-Jia Liu, and David Kwiatkowski. This work was recently published in the journal Oncogene in January 2021.

Publication for Krinio Giannikou:

Zarei M, Giannikou K, Du H, Liu HJ, Duarte M, Johnson S, Nassar AH, Widlund HR, Henske EP, Long HW, and Kwiatkowski DJ. 2021. MITF is a driver oncogene and potential therapeutic target in kidney angiomyolipoma tumors through transcriptional regulation of CYR61. Oncogene 40(1):112-126. doi: 10.1038/s41388-020-01504-8. Epub 2020 Oct 20. PMID: 33082558; PMCID: PMC7796905. https://pubmed.ncbi.nlm.nih.gov/33082558/

Publication for Mahsa Zarei:

Zarei M, Du H, Nassar AH, Yan RE, Giannikou K, Johnson SH, Lam HC, Henske EP, Wang Y, Zhang T, Asara J, and Kwiatkowski DJ. 2019. Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion. J Exp Med 216(11):2635-2652. doi: 10.1084/jem.20190251. Epub 2019 Sep 10. PMID: 31506280; PMCID: PMC6829598.https://pubmed.ncbi.nlm.nih.gov/31506280/

Links:

Abstracts for Dr. Giannikou

Public and Technical Abstracts: Epigenetic Analysis of TSC Tumors to Identify Novel Therapeutic Targets

Abstracts for Dr. Zarei

Public and Technical Abstracts: Targeting Transcriptional Addiction for the Treatment of TSC

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Last updated Friday, May 14, 2021