Alexander Pertsemlidis, PhD

  • Rank: Associate Professor
  • Department: Pediatrics
  • Office: 3.100.22
  • Location: Greehey CCCRI
  • Tel: 1.210.562.9062

 

Our research interests integrate computational biology, cancer biology and genetics. We study regulatory RNA molecules called non-coding RNAs (called that because they do not code for proteins), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), and how they regulate cancer cell growth and response to anti-cancer drugs.

 

Neuroblastoma –

Neuroblastoma is the most common extracranial solid tumor in childhood. The majority of children over 1 year of age present with disseminated metastases – these are aggressive, drug resistant and generally incurable. Treated with chemotherapy, surgery, radiation therapy, and/or stem cell transplantation, these children typically experience rapid recurrence of a more aggressive neuroblastoma. This demands the development of novel and more effective therapeutic approaches.

 

Our beliefs:

  • nature has already developed elegant but non-obvious solutions to most problem facing modern medicine,
  • there may be many different solutions to  the same problem, and
  • things that look the same at the tissue  level may look very different at the molecular level.

 

Goals:

  • develop sensitive, non-invasive methods for early cancer detection, and
  • identify new drugs targeting specific adult and pediatric cancer subtypes, either directly or in combination with traditional therapeutic agents.

 

Projects:

  • ncRNA regulation of cell viability and drug response in neuroblastoma
  • Trisomy 21 and protection against neuroblastoma
  • Therapeutic miRNAs in combination with conventional chemotherapy
  • Molecular sensors for detecting cancer at the single-cell Level
  • Separating tumor and host miRNAs through TU-tagging
  • Therapeutic regulation of the PI3K and Wnt signaling pathways

 

Results:

  • miRNA, lncRNA and mRNA expression signatures of cancer cells and normal cells,
  • interaction networks between miRNAs, lncRNAs and mRNAs,
  • ncRNAs and their regulatory targets characterized in vitro, in vivo and in silico,
  • functional relationships between ncRNAs and disease, and
  • candidate biomarkers, therapeutic targets and therapeutic agents.

 

 

Alexander Pertsemlidis, PhD, joined the Greehey Children’s Cancer Research Institute in August of 2011 with major faculty responsibilities as a Principal Investigator in the areas of Cancer Genetics, Experimental Therapeutics and Molecular Oncogenesis and Associate Professor in the Departments of Pediatrics and Cellular and Structural Biology. He received his doctoral degree from the University of California, Berkeley and completed two post-doctoral fellowships at UT Southwestern Medical Center, Dallas, Texas.

 

 

My research program is centered on the study of microRNA regulation of cell viability and drug response in cancer, and is aimed at developing sensitive, non-invasive methods for early cancer detection and novel therapeutic agents targeting specific cancer subtypes. We have four ongoing projects: microRNA regulation of (1) drug response in non-small cell lung carcinoma (NSCLC), (2) cell viability in neuroendocrine tumors, (3) cell viability of KRAS-dependent lung cancers, and (4) PI3K and drug response in PI3K-driven oncogenesis. All of the projects integrate in silico, in vitro and in vivo approaches.

In an unbiased and comprehensive approach, we have combined a high-throughput screening platform with a library of chemically synthesized microRNA mimics and inhibitors. We have used this platform to identify mimics and inhibitors that reduce cell viability in general, and those that specifically sensitize cells to taxanes.

We have identified several miRNAs for which over-expression or inhibition has a dramatic and selective effect on cell viability or drug response. We have demonstrated that miR-337-3p mimic sensitizes NSCLC cells to taxanes. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p by enhancing taxane-induced arrest in the G2 phase of the cell cycle. We have also identified an inhibitor of miR-139-5p as a potent and selective regulator of SCLC cell viability. Inhibiting miR-139-5p decreases SCLC cell viability by over 80%, but has a minimal cytotoxic effect on that of NSCLCs or immortalized human bronchial epithelial cells. We are currently investigating the targets of miR-139-5p that mediate its effect on SCLC cell viability.

An inhibitor of miR-10a has the opposite effect and increases cell viability in NSCLC cells. Manipulation of miR-10a levels alters cellular response to paclitaxel and results in significant changes in both mRNA and protein levels of its predicted target, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which has been shown to play a major role in proliferation and survival in a number of human cancers and is a significant therapeutic target. In NSCLC patients, high miR-10a levels correlate with longer overall survival, suggesting that miR-10a levels may be correlated with patient response to chemotherapy, especially PI3K inhibitors.

These investigations have contributed to our understanding of microRNA roles in and beyond lung cancer pathogenesis and have established a foundation on which we can build in several orthogonal directions. We are extending the work to drugs with different mechanisms of action, to different histological subtypes of lung cancer, and finally to different cancer types, including breast cancer, neuroblastoma and pheochromocytoma. There are few cancers for which detection is so efficient and drug response so thorough that a better understanding of the mechanisms by which microRNAs control tumor cell survival and how they can serve as the basis for improved diagnostic strategies or increased therapeutic efficacy cannot be achieved.

 

 

Computational Biology
Given the steadily increasing use of high-throughput methods in biomedical research, modern biologists need to understand both how biological data is collected and how to express biological problems in terms of algorithms and data structures. I believe that students should combine combine wet-lab and dry-lab work in both their courses and research projects. Such interdisciplinary training in computational and systems biology is appropriate to how modern biomedical research is evolving.

Lung Cancer

Neuroblastoma

Non-coding RNA Biology
The major focus of my lab is on investigating roles of non-coding RNA regulation in cancer pathogenesis, specifically: (1) non-coding RNA regulation of cell viability, and (2) non-coding RNA regulation of drug response. The long term goals of these projects are the identification of ncRNAs for which serum expression is a biomarker of either the presence or progression of tumors or of the likely response of a tumor to drug treatment, and of ncRNA mimics or inhibitors that can be delivered as therapeutic agents. Both projects integrate in silico, in vitro and in vivo approaches.

Statistical Genetics
Development and application of statistical methods to test associations between genotype and phenotype and testing the conventional wisdom that common disease is explained by common variants. Power and sample size calculations, kinship calculation, and statistical tests for association.

 

 

Federal


Funding Agency National Cancer Institute
Title Cancer Biology Training Program
Status Active Active
Period 8/2001-7/2016
Role Contributor
Grant Detail The goal of the Cancer Biology Training Program (PI & Director: LuZhe Sun, PhD) is to educate the next generation of cancer researchers to meet the growing demands for scientists trained in multiple facets of cancer biology. The training program has 35 preceptors from 12 departments institution-wide who are affiliated with the IMGP Cancer Biology Track and the Cancer Therapy and Research Center (CTRC), UTHSCSAs NCI-designated Cancer Center.

Funding Agency Department of Defense
Title Identifying microRNAs that regulate neuroblastoma cell differentiation
Status Active Active
Period 9/2013-2/2016
Role Co-Investigator
Grant Detail Our goal is to comprehensively identify neuroblastoma differentiation-inducing microRNAs in a high-throughput manner. By combining a functional high-content screening approach and a library of microRNA mimics synthetic oligonucleotides used to raise the intracellular levels of microRNAs we will directly identify microRNA mimics that are potent inducers of neuroblastoma cell differentiation. The identified differentiation-inducing microRNA mimics have direct potential to be developed into oligonucleotide-based therapeutic agents for neuroblastoma differentiation therapy.

Private

Funding Agency Mirna Therapeutics
Title Therapeutic miRNAs in combination with conventional chemotherapy
Status Active Active
Period 11/2013-5/2016
Role Principal Investigator

State

Funding Agency Cancer Prevention & Research Institute of Texas (RP 140105)
Title Cancer Research Training Grant
Status Active Active
Period 3/2014-2/2016
Role Co-Principal Investigator
Grant Detail Years 4-5. This Research Training Award (RTA) provides support for predoctoral and postdoctoral (post-residency MD fellows and basic science PhD) trainees as well as undergraduate students (summer research internship program) to receive training in cancer research. The overall goal is for trainees to be exposed to all aspects of cancer research (basic, translational and clinical) so that they will have a strong appreciation of, and progress on to independent and productive careers in cancer research. This is a continuation of an earlier RTA (RP 101491; 07/13/2010 02/28/2014).

Funding Agency IIMS/CTSA/UTSA/Greehey CCRI
Title Cancer Research Training Grant
Status Active Active
Period 3/2014-2/2016
Role Co-Principal Investigator
Grant Detail Years 4-5. This Research Training Award (RTA) provides support for predoctoral and postdoctoral (post-residency MD fellows and basic science PhD) trainees as well as undergraduate students (summer research internship program) to receive training in cancer research. The overall goal is for trainees to be exposed to all aspects of cancer research (basic, translational and clinical) so that they will have a strong appreciation of, and progress on to independent and productive careers in cancer research. This is a continuation of an earlier RTA (RP 101491; 07/13/2010 02/28/2014).