Boards, Advisory Committees, Professional Organizations
Voting Member, Pharmacy and Therapeutics Committee, Stanford Hospital and Clinics (2020 - Present)
Residency: Stanford University Anesthesiology Residency (2020) CA
Internship: Stanford University Internal Medicine Residency (2017) CA
Doctor of Medicine, University of California San Francisco (2016)
Doctor of Philosophy, University of California San Francisco, Chemistry and Chemical Biology (2014)
Bachelor of Science, Haverford College, Biology (major), Biochemistry (concentration), and Mathematics (minor) (2009)
Georgios Skiniotis, Postdoctoral Research Mentor
Current Research and Scholarly Interests
Pharmacology and structural biology of G protein-coupled receptors
Drugging MYCN through an Allosteric Transition in Aurora Kinase A.
2014; 26 (3): 414–27
MYC proteins are major drivers of cancer yet are considered undruggable because their DNA binding domains are composed of two extended alpha helices with no apparent surfaces for small-molecule binding. Proteolytic degradation of MYCN protein is regulated in part by a kinase-independent function of Aurora A. We describe a class of inhibitors that disrupts the native conformation of Aurora A and drives the degradation of MYCN protein across MYCN-driven cancers. Comparison of cocrystal structures with structure-activity relationships across multiple inhibitors and chemotypes, coupled with mechanistic studies and biochemical assays, delineates an Aurora A conformation-specific effect on proteolytic degradation of MYCN, rather than simple nanomolar-level inhibition of Aurora A kinase activity.
View details for DOI 10.1016/j.ccr.2014.07.015
View details for PubMedID 25175806
BRAF Status in Personalizing Treatment Approaches for Pediatric Gliomas.
Clinical cancer research
2016; 22 (21): 5312-5321
Alteration of the BRAF/MEK/MAPK pathway is the hallmark of pediatric low-grade gliomas (PLGGs), and mTOR activation has been documented in the majority of these tumors. We investigated combinations of MEK1/2, BRAF(V600E) and mTOR inhibitors in gliomas carrying specific genetic alterations of the MAPK pathway.We used human glioma lines containing BRAF(V600E) (adult high-grade: AM-38, DBTRG, PLGG: BT40), or wild-type BRAF (pediatric high-grade: SF188, SF9427, SF8628) and isogenic systems of KIAA1549:BRAF-expressing NIH/3T3 cells and BRAF(V600E)-expressing murine brain cells. Signaling inhibitors included everolimus (mTOR), PLX4720 (BRAF(V600E)), and AZD6244 (MEK1/2). Proliferation was determined using ATP-based assays. In vivo inhibitor activities were assessed in the BT40 PLGG xenograft model.In BRAF(V600E) cells, the three possible doublet combinations of AZD6244, everolimus, and PLX4720 exhibited significantly greater effects on cell viability. In BRAF(WT) cells, everolimus + AZD6244 was superior compared with respective monotherapies. Similar results were found using isogenic murine cells. In KIAA1549:BRAF cells, MEK1/2 inhibition reduced cell viability and S-phase content, effects that were modestly augmented by mTOR inhibition. In vivo experiments in the BRAF(V600E) pediatric xenograft model BT40 showed the greatest survival advantage in mice treated with AZD6244 + PLX4720 (P < 0.01).In BRAF(V600E) tumors, combination of AZD6244 + PLX4720 is superior to monotherapy and to other combinatorial approaches. In BRAF(WT) pediatric gliomas, everolimus + AZD6244 is superior to either agent alone. KIAA1549:BRAF-expressing tumors display marked sensitivity to MEK1/2 inhibition. Application of these results to PLGG treatment must be exercised with caution because the dearth of PLGG models necessitated only a single patient-derived PLGG (BT40) in this study. Clin Cancer Res; 22(21); 5312-21. ©2016 AACR.
View details for PubMedID 27217440
N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells.
2016; 29 (4): 536-547
MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance, and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention.
View details for DOI 10.1016/j.ccell.2016.03.001
View details for PubMedID 27050099
A new "angle" on kinase inhibitor design: Prioritizing amphosteric activity above kinase inhibition.
Molecular & cellular oncology
2015; 2 (2)
The MYCN oncoprotein has remained an elusive target for decades. We recently reported a new class of kinase inhibitors designed to disrupt the conformation of Aurora kinase A enough to block its kinase-independent interaction with MYCN, resulting in potent degradation of MYCN. These studies provide proof-of-principle for a new method of targeting enzyme activity-independent functions of kinases and other enzymes.
View details for DOI 10.4161/23723556.2014.975641
View details for PubMedID 27308435
The prenatal origins of cancer
NATURE REVIEWS CANCER
2014; 14 (4): 277-289
The concept that some childhood malignancies arise from postnatally persistent embryonal cells has a long history. Recent research has strengthened the links between driver mutations and embryonal and early postnatal development. This evidence, coupled with much greater detail on the cell of origin and the initial steps in embryonal cancer initiation, has identified important therapeutic targets and provided renewed interest in strategies for the early detection and prevention of childhood cancer.
View details for DOI 10.1038/nrc3679
View details for Web of Science ID 000333406200015
View details for PubMedID 24599217
Epithelial carbonic anhydrases facilitate P-CO2 and pH regulation in rat duodenal mucosa
JOURNAL OF PHYSIOLOGY-LONDON
2006; 573 (3): 827-842
The duodenum is the site of mixing of massive amounts of gastric H+ with secreted HCO3-, generating CO2 and H2O accompanied by the neutralization of H+. We examined the role of membrane-bound and soluble carbonic anhydrases (CA) by which H+ is neutralized, CO2 is absorbed, and HCO3- is secreted. Rat duodena were perfused with solutions of different pH and PCO2 with or without a cell-permeant CA inhibitor methazolamide (MTZ) or impermeant CA inhibitors. Flow-through pH and PCO2 electrodes simultaneously measured perfusate and effluent pH and PCO2. High CO2 (34.7 kPa) perfusion increased net CO2 loss from the perfusate compared with controls (pH 6.4 saline, PCO2 approximately 0) accompanied by portal venous (PV) acidification and PCO2 increase. Impermeant CA inhibitors abolished net perfusate CO2 loss and increased net HCO3- gain, whereas all CA inhibitors inhibited PV acidification and PCO2 increase. The changes in luminal and PV pH and [CO2] were also inhibited by the Na+-H+ exchanger-1 (NHE1) inhibitor dimethylamiloride, but not by the NHE3 inhibitor S3226. Luminal acid decreased total CO2 output and increased H+ loss with PV acidification and PCO2 increase, all inhibited by all CA inhibitors. During perfusion of a 30% CO2 buffer, loss of CO2 from the lumen was CA dependent as was transepithelial transport of perfused 13CO2. H+ and CO2 loss from the perfusate were accompanied by increases of PV H+ and tracer CO2, but unchanged PV total CO2, consistent with CA-dependent transmucosal H+ and CO2 movement. Inhibition of membrane-bound CAs augments the apparent rate of net basal HCO3- secretion. Luminal H+ traverses the apical membrane as CO2, is converted back to cytosolic H+, which is extruded via NHE1. Membrane-bound and cytosolic CAs cooperatively facilitate secretion of HCO3- into the lumen and CO2 diffusion into duodenal mucosa, serving as important acid-base regulators.
View details for DOI 10.1113/jphysiol.2006.107581
View details for Web of Science ID 000239154200018
View details for PubMedID 16556652