Assistant Professor, Department of Biochemistry and Microbiology, UAMS College of Medicine, Member, Winthrop P. Rockefeller Cancer Institute
Q. What is your relationship to cancer?
A. My research focuses on non-Receptor Tyrosine Kinase (nRTK) mediated TGFβ/SMAD signaling in tumorigenesis and metastasis, and aims to discover novel therapeutic mechanisms for treating triple negative breast cancer (TNBC). I am a member of the Epigenetics, Cancer, Systems Biology and Proteomics Group of the Winthrop P. Rockefeller Cancer Institute (WPRCI). It is an exciting research program that brings an array of expertise together to leverage our effort to defeat cancer. My lab will apply systems-biology approaches to quantitatively understand healthy and cancer cell signaling to develop new precision medicine therapies for improving metastatic TNBC patient survival and quality of life.
Q. What are you currently working on in the lab?
A. The switch of anti-tumorigenic and anti-metastatic function of TGF-β/SMAD4 signaling to a metastatic- promoting factor remains a long-standing biological paradox in metastatic breast cancer. Recently, we showed that BRK, a non-receptor protein tyrosine kinase, promotes metastatic potential by phosphorylating SMAD4 in breast epithelial cells. The phosphorylated-SMAD4 promotes interactions with chromatin remodeling complexes. These chromatin remodelers are master epigenetic regulators that repress transcription and have been implicated in breast cancer pathogenesis. Currently, we are determining how phosphorylated-SMAD4 coordinates with epigenetic modifiers to reprogram gene expression in metastatic TNBC cells. We are also synthesizing a BRK-specific proteolysis targeting chimera (PROTAC) to deplete BRK to restore the anti-tumorigenic and anti-metastatic functions of the TGF-β/SMAD signaling to prevent TNBC metastasis.
Q. What do you hope to contribute to the Cancer Institute?
A. I investigated the molecular mechanism of tumorigenesis and metastasis of breast cancer and I received advanced training on proteomics, chromatin biology and system biology during my postdoctoral training. I believe that mass-spec based proteomics is an essential tool for studying signal transduction pathways and it can provide molecular insight of complex biological processes. I am enthusiastic to collaborate and support other Cancer Institute members to apply proteomics in their research programs. I do believe our collaborative successes would be beneficial in our pursuit of NCI designation for the Winthrop P. Rockefeller Cancer Institute.
More about Sayem Miah, Ph.D.
I recently joined UAMS as an assistant professor in the Department of Biochemistry and Molecular Biology and am a member of the Winthrop P. Rockefeller Cancer Institute. I am very excited to be a member of this Cancer Institute and its long-standing reputation as a cancer care provider for the people of Arkansas. UAMS is an ideal place to translate basic research into translational research. My laboratory is studying the non-receptor tyrosine kinases (nRTKs) in order to restore anti-tumorigenic and anti-metastatic functions of the TGFβ/SMAD signaling to prevent TNBC metastasis. TNBC is particularly prone to aggressive metastases, for reasons that are still poorly understood. Protein kinase inhibitors are a major focus of the current oncology market and there are >35 FDA-approved options for drugs that target tyrosine kinases. This makes nRTKs a viable and promising target for tackling metastasis in TNBC. Intriguingly, the inhibition of the kinase activity of nRTKs did not always yield anticancer efficacy—suggesting an alternate kinase-independent role for nRTKs in tumorigenesis and metastasis. Thus, we are synthesizing a PROTAC to deplete nRTKs to restore the anti-tumorigenic and anti-metastatic functions of the TGFβ/SMAD signaling to prevent TNBC metastasis. I am collaborating with pharmaceutical chemist to synthesize BRK specific PROTAC and with an oncologist for a future investigator-initiated clinical trial.
For this research, my laboratory will extensively use advanced proteomics, biochemical, genomic and molecular biology techniques to elucidate molecular mechanism of cancer metastasis. During my master’s degree training in Medical Biology at the University of Linkoping, I gained proficiency with an array of molecular biology techniques to study the underlying biology of disease. My interest in disease biology led me to pursue graduate work studying the role and mechanism of BRK in tumorigenesis. I carried out my doctoral training in the laboratory of Dr. Kiven E. Lukong at the University of Saskatchewan, Canada.
During my postdoctoral training (Washburn Lab, Stowers Institute for Medical Research, Kansas City, MO), I combined my new and prior skills, and have carved out a unique interdisciplinary research program that has uncovered unprecedented opportunities to study BRK regulating TGF-β/SMAD signaling in metastatic breast cancer. I took a “systems-wide” interrogation approach for studying signaling networks using advanced chemical proteomic, biochemical, and genomic techniques to uncover molecular biology of tumorigenesis. I demonstrated that activated BRK directly interacts with and phosphorylates SMAD4 and causes proteasomal degradation to repress tumor suppressor gene FRK and to increase expression of the mesenchymal markers SNAIL and SLUG and published in Science Advance (https://pubmed.ncbi.nlm.nih.gov/31681835/). This research on BRK and TGF-β signaling that I conducted at Stowers led to my interest in synthesis of BRK-PROTAC to deplete BRK to tackle TNBC what I will pursue here at UAMS.