Alejandro Sweet-Cordero, MD

Associate Professor
Department of Pediatrics
Benioff Chair of Child Health
Division of Hematology and Oncology
+1 415 476-7781
Research Description: 

Our goal is to identify novel therapeutic approaches for cancer that target the genetic mutations and altered signaling networks that are specific to cancer cells. We use functional genomics applied to mouse and human systems (genetically engineered models, patient derived xenografts) to understand the transcriptional networks that regulate the outcome of specific oncogenic mutations and to identify new approaches for cancer therapy. We have two primary disease interests: lung cancer and pediatric sarcomas.

In our lung cancer work, we are heavily focused on using functional genomic approaches to study how KRAS functions as an oncogene. For example, we carried out one of the first mouse and human combined screens to identify Wt1 as a synthetic vulnerability for KRAS in NSCLC (Vicent et al, 2010, JCI). More recently, we described a key role of oncogenic Ras in regulation of the response to nutrient stress (Gwinn et al 2018, Cancer Cell). We are funded by the NCI Ras initiative as part of a multi-PI effort to identify novel synthetic lethal genes in the Ras pathway (collaboration with the Bassik and Jackson labs, both at Stanford University). We are also interested in identifying and characterizing the role of tumor-propagating cells (also called cancer stem cells) in NSCLC. Using a combination of mouse and human systems, we identified a key role for Notch3 as a self-renewal pathway in mouse and human NSCLC (Zheng et al, 2013, Cancer Cell). Ongoing projects are seeking to identify other KRAS specific vulnerabilities using 2D and 3D systems in both mouse and human. We are also exploring the use of single cell genomics to further evaluate intra-tumor heterogeneity.

In our sarcoma work, we are interested in mechanisms driving Osteosarcoma and Ewing sarcoma progression. These diseases provide an interesting contrast as clinically they are similar but from a genomic standpoint they are quite distinct. We recently identified EWSAT1 as the first lncRNA involved in the pathogenesis of Ewing sarcoma (Howarth et al, JCI, 2014). Ongoing work is focused on understanding how lncRNAs regulate the oncogenic capacity of the EWS/FLI1 fusion. In osteosarcoma, have defined genome-informed targeted therapies using a combination of Whole-genome sequencing and RNAsequencing (Sayles and Breese et al Cancer Discovery, 2019).

We make extensive use of computational genomic approaches in our work and we have wide experience in generating and using next-generation sequencing data for gene and network discovery. We are actively involved in a multidisciplinary effort to apply next-generation sequencing (WGS/RNAseq etc.) to advance the care of relapsed and other high-risk pediatric cancer patients at UCSF/Benioff Children’s Hospitals (San Francisco and Oakland). To date, our laboratory has sequenced over 150 pediatric tumors by Whole Genome Sequencing and RNAseq. These datasets provide ample research opportunity for trainees interested in the intersection of cancer biology, functional genomics and computational biology.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Developmental & Stem Cell Biology
Research Summary: 
Functional genomic and genetic analysis of therapy resistance, tumor heterogeneity and oncogenic mechanisms in cancer.

Websites

Publications: 

Oncoprotein-specific molecular interaction maps (SigMaps) for cancer network analyses.

Nature biotechnology

Broyde J, Simpson DR, Murray D, Paull EO, Chu BW, Tagore S, Jones SJ, Griffin AT, Giorgi FM, Lachmann A, Jackson P, Sweet-Cordero EA, Honig B, Califano A

NUP98-NSD1 Driven MDS/MPN in Childhood Masquerading as JMML.

Journal of pediatric hematology/oncology

Behnert A, Lee AG, Young EP, Breese MR, Leung SG, Behroozfard I, Maruffi M, Sweet-Cordero EA, Dvorak CC, Chu J, Stieglitz E

Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities.

Cancer discovery

Kelly MR, Kostyrko K, Han K, Mooney NA, Jeng EE, Spees K, Dinh PT, Abbott KL, Gwinn DM, Sweet-Cordero EA, Bassik MC, Jackson PK

Engineering a potent receptor superagonist or antagonist from a novel IL-6 family cytokine ligand.

Proceedings of the National Academy of Sciences of the United States of America

Kim JW, Marquez CP, Sperberg RAP, Wu J, Bae WG, Huang PS, Sweet-Cordero EA, Cochran JR

Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures.

PLoS computational biology

Pfeil J, Sanders LM, Anastopoulos I, Lyle AG, Weinstein AS, Xue Y, Blair A, Beale HC, Lee A, Leung SG, Dinh PT, Shah AT, Breese MR, Devine WP, Bjork I, Salama SR, Sweet-Cordero EA, Haussler D, Vaske OM