Associate Professor of Medicine
Medicine (Division of Cancer Medicine and Blood Disease)
Keck School of Medicine
- Cancer Cell Biology
- Cancer Treatment
- Circulating Tumor Cells
- Cancer Stem Cell Biology
- Telomerase Therapeutics
Research OverviewDr. Goldkorn’s laboratory-based research program focuses on developing the therapeutic and biomarker potential of circulating tumor cells, cancer stem cells, and telomerase. Graduate students, postdocs and medical students in the laboratory conduct experiments ranging from basic molecular research to translational medicine assays for clinical trials. These research activities synergize with our clinical activities and provide unique opportunities to translate our laboratory and clinical advances into better care for our patients.
Research: Cancer is marked by formidable heterogeneity at every level, from patients, to tumor cells, to signaling pathways. To address this challenge, our research program focused on developing the therapeutic and prognostic potential of circulating tumor cells, cancer stem cells, and telomerase – three areas that offer unique opportunities to better understand and surmount cancer heterogeneity.
Circulating Tumor Cells (CTCs): CTCs are cancer cells shed by solid tumors into the bloodstream, and their analysis can address cancer heterogeneity by identifying molecular drivers unique to an individual patient’s tumor. CTC sampling thus facilitates targeted selection of optimal therapy and enables subsequent monitoring of response to that therapy. Moreover, CTC analysis allows real time tracking of cancer plasticity as tumor cells evolve through various lines of therapy, thus elucidating mechanisms of cancer resistance and identifying potential new therapeutic targets. Our group developed a slot microfilter that captures live CTCs from whole blood based on differential size and deformability, allowing for their molecular characterization. We use the microfilter and other CTC enrichment methods to collect CTCs from patients and from mouse xenograft models for transcriptome analysis in parallel with primary tumor and metastasis cells from the same hosts, enabling identification of differentially expressed or mutated genes that may drive cancer dissemination and progression. These techniques have been expanded to the clinical realm: Our team led the CTC correlative studies for a large phase III multi-center prostate cancer trial and demonstrated the prognostic value of CTC enumeration and CTC telomerase activity in this setting. CTC analysis is now being used in several other clinical trial settings: for example, NextGen sequencing of CTCs to identify somatic single nucleotide variants (SNVs) in a new phase III multicenter prostate cancer trial now being launched. Recently, we founded a CTC Research Core at USC Norris, which houses many of our CTC research activities and encourages new collaborations.
Cancer Stem Cells (CSCs): In recent years, cancer stem cells (CSCs), a subset of tumor cells with uniquely aggressive, highly tumorigenic, drug resistant properties, have been shown to mediate cancer recurrence and drug resistance. Our laboratory discovered that cancer cells could cyclically lose and regain CSC properties, a phenotypic plasticity with significant implications for therapeutic attempts to target CSCs. In subsequent studies, we demonstrated that PI3K/AKT (upstream) partners with β-catenin/CBP (downstream) to mediate this phenotypic plasticity in and out of a CSC state. Ongoing mechanistic studies of phenotypic plasticity are employing microarray analyses of differential gene expression and promoter methylation to identify additional drivers of plasticity. In a separate project, we analyzed RNA from a cohort of 300 radical prostatectomy specimens and found that expression of AXIN2, a transcriptional target and feedback regulator of β-catenin, is predictive of cancer recurrence after prostatectomy. These findings were validated in additional external datasets, and in vitro work in our laboratory demonstrated that AXIN2 expression levels significantly affect invasiveness and tumor formation by prostate cancer cells. Currently, we are continuing to validate AXIN2 as a prognostic biomarker in additional data sets, and to pursue mechanistic studies aimed at elucidating the transcriptional targets and protein partners of AXIN2 in prostate cancer.
Telomerase: Telomerase is a reverse transcriptase ribonucleoprotein that protects and lengthens telomeres at the ends of chromosomes. Telomerase activation is an essential step in the formation and progression of >90% of all malignancies and therefore may constitute an effective therapeutic target across heterogeneous malignancies. During my postdoctoral research training with Elizabeth Blackburn at UCSF, we explored the therapeutic potential of telomerase interference, a technique that reprograms the active telomerase in cancer cells and leads to rapid apoptosis. Currently, my laboratory seeks to advance telomerase interference to in vivo models and ultimately to a novel cancer therapeutic. Using patient prostatectomy specimens, we identified subpopulations of cancer stem cells (CSCs) in prostate tumors that possessed extremely high telomerase levels relative to non-CSC tumor cells, and we used telomerase interference to neutralize these cells. Currently, we are developing a novel strategy for telomerase interference using a small molecule designed to specifically bind and reprogram telomerase. This approach has the key advantage of potentially being systemically deliverable as an effective new cancer therapeutic.