Research Summary

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.  Our research spans the continuum from basic discovery to clinical application, done in a dynamic and interactive environment that is highly collaborative. 

In our lung cancer work, we use functional genomic approaches to study how KRAS functions as an oncogene and to identify novel therapeutic opportunities. We performed one of the first mouse and human in vivo functional screens to identify WT1 loss as a synthetic vulnerability for KRAS-driven NSCLC (Vicent et al, 2010, JCI). More recently, we described a key role of oncogenic KRAS in regulation of the response to nutrient stress (Gwinn et al 2018, Cancer Cell). Through a multidisciplinary collaboration we have performed a high-throughput proteomic and genomics screen to characterize novel KRAS specific combinatorial vulnerabilities (Kelly, Kostyrko and Han, Cancer Discovery 2020). 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).  We also have identified novel methods for targeting tumor-stroma interactions in lung cancer (Kim and Marquez et al, Nature Medicine, 2019). Ongoing projects are seeking to identify other KRAS specific vulnerabilities using 2D and 3D systems in both mouse and human. We are also using single-cell sequencing and other genomics approaches (ATACseq, etc) to study the role of TPCs in lung cancer. 

In our sarcoma work, we study mechanisms driving sarcoma progression using in vivo patient-derived xenograft models. We identified EWSAT1 as the first lncRNA involved in the pathogenesis of Ewing sarcoma (Howarth et al, JCI, 2014) and ongoing work is focused on understanding how lncRNAs regulate oncogenesis in sarcomas. Recently we described how genomic analysis of osteosarcoma can help identify targeted therapies for this disease (Sayles and Breese et al, Cancer Discovery 2019). Our sarcoma work is facilitated by access to a large collection of patient-derived xenograft models and to primary tumor samples.  We are using these models to explore the genomic evolution of sarcomas and define novel therapeutics that are informed by the alterations present in individual tumors.

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. These datasets provide ample research opportunity for trainees interested in the intersection of cancer biology, functional genomics and computational biology. 

E. Alejandro Sweet-Cordero is a member of both the Biomedical Sciences (BMS) and the Pharmaceutical Sciences and Pharmacogenomics (PSPG) graduate programs. The laboratory is also affiliated with the Bakar Institute for Computational Health Sciences at UCSF. Alejandro Sweet-Cordero also directs the Molecular Oncology Initiative at UCSF and has expertise in the clinical implementation of precision medicine for adult and pediatric cancer.

Individuals interested in joining our research group are encouraged to forward a Curriculum Vitae to [email protected]. For more information please refer to the lab website at sweetcorderolab.ucsf.edu
 

Research Funding

  • April 1, 2018 - March 31, 2023 - Development of novel protein-based therapeutics for lung cancer , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA225103
  • March 13, 2017 - February 28, 2022 - Role of long non-coding RNAs in sarcoma pathogenesis , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA211657
  • September 2, 2015 - July 31, 2019 - Using Protein Interaction Networks and Combinatorial Screens to target KRAS driven cancer , Co-Investigator . Sponsor: NIH, Sponsor Award ID: U01CA199216

Education

Stanford University, B.S., 06/1989, Biology
Stanford University, B.A., 06/1989, Anthropology
University of California San Francisco, M.D., 06/1995, Medicine
University of California San Francisco, Residency, 06/1998, Pediatrics
Dana Farber Cancer Institute/Boston Children’s Hospital, Subspecialty training, 06/2002, Pediatric Hematology/Oncology

Honors & Awards

  • 1989
    Stanford University Firestone Award for Excellence in Undergraduate Research
  • 2006
    Sidney Kimmel Scholar Award
  • 2007
    Doris Duke Clinical Scientist Award
  • 2008
    Rita Allen Scholar Award
  • 2009
    Morgridge Scholar Award

Selected Publications

  1. González Díaz EC, Lee AG, Sayles LC, Feria C, Sweet-Cordero EA, Yang F. A 3D Osteosarcoma Model with Bone-Mimicking Cues Reveals a Critical Role of Bone Mineral and Informs Drug Discovery. Adv Healthc Mater. 2022 Jun 29; e2200768.  View on PubMed
  2. Roman M, Hwang E, Sweet-Cordero EA. Synthetic Vulnerabilities in the KRAS Pathway. Cancers (Basel). 2022 Jun 08; 14(12).  View on PubMed
  3. Solomon PE, Kirkemo LL, Wilson GM, Leung KK, Almond MH, Sayles LC, Sweet-Cordero EA, Rosenberg OS, Coon JJ, Wells JA. Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction in Interferon-β Autocrine Stimulation. Mol Cell Proteomics. 2022 May 18; 21(7):100247.  View on PubMed
  4. Van Loon K, Mohar A, Unger-Saldaña K, Potter MB, Sweet-Cordero EA, Breithaupt L, Espinosa-Tamez P, Sepúlveda-Amor J, Lajous M. Salud Publica Mex. 2022 Feb 25; 64(1):100-104.  View on PubMed
  5. Youn M, Smith SM, Lee AG, Chae HD, Spiteri E, Erdmann J, Galperin I, Jones LM, Donato M, Abidi P, Bittencourt H, Lacayo N, Dahl G, Aftandilian C, Davis KL, Matthews JA, Kornblau SM, Huang M, Sumarsono N, Redell MS, Fu CH, Chen IM, Alonzo TA, Eklund E, Gotlib J, Khatri P, Sweet-Cordero EA, Hijiya N, Sakamoto KM. Comparison of the Transcriptomic Signatures in Pediatric and Adult CML. Cancers (Basel). 2021 Dec 14; 13(24).  View on PubMed
  6. Shah AT, Azad TD, Breese MR, Chabon JJ, Hamilton EG, Straessler K, Kurtz DM, Leung SG, Spillinger A, Liu HY, Behroozfard IH, Wittber FM, Hazard FK, Cho SJ, Daldrup-Link HE, Vo KT, Rangaswami A, Pribnow A, Spunt SL, Lacayo NJ, Diehn M, Alizadeh AA, Sweet-Cordero EA. A Comprehensive Circulating Tumor DNA Assay for Detection of Translocation and Copy-Number Changes in Pediatric Sarcomas. Mol Cancer Ther. 2021 10; 20(10):2016-2025.  View on PubMed
  7. Behnert A, Lee AG, Young EP, Breese MR, Leung SG, Behroozfard I, Maruffi M, Sweet-Cordero EA, Dvorak CC, Chu J, Stieglitz E. NUP98-NSD1 Driven MDS/MPN in Childhood Masquerading as JMML. J Pediatr Hematol Oncol. 2021 08 01; 43(6):e808-e811.  View on PubMed
  8. Levinson A, Lee AG, Martell HJ, Breese MR, Zaloudek C, Van Ziffle J, Laguna B, Leung SG, Chen MD, Chen LM, Pfeil J, Ladwig NR, Shah AT, Behroozfard I, Rao AA, Salama SR, Sweet-Cordero EA, Stieglitz E. Complete Response to PD-1 Inhibition in an Adolescent With Relapsed Clear Cell Adenocarcinoma of the Cervix Predicted by Neoepitope Burden and APOBEC Signature. JCO Precis Oncol. 2020; 4.  View on PubMed
  9. Kostyrko K, Sweet-Cordero EA. An Expanded Tool Kit for Modeling the Oncogenic Functions of KRAS. Cancer Discov. 2020 11; 10(11):1626-1628.  View on PubMed
  10. Hawkins C, Pfister S, Jones DTW, Shah NN, Gilbertson RJ, Sweet-Cordero EA, Dyer MA, Mossé YP, Haber M, DuBois SG. Advances and Challenges in Pediatric and Childhood Cancers. Cancer Cell. 2020 10 12; 38(4):429-432.  View on PubMed
  11. 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. Oncoprotein-specific molecular interaction maps (SigMaps) for cancer network analyses. Nat Biotechnol. 2021 02; 39(2):215-224.  View on PubMed
  12. 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. Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities. Cancer Discov. 2020 12; 10(12):1950-1967.  View on PubMed
  13. Kim JW, Marquez CP, Sperberg RAP, Wu J, Bae WG, Huang PS, Sweet-Cordero EA, Cochran JR. Engineering a potent receptor superagonist or antagonist from a novel IL-6 family cytokine ligand. Proc Natl Acad Sci U S A. 2020 06 23; 117(25):14110-14118.  View on PubMed
  14. 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. Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures. PLoS Comput Biol. 2020 04; 16(4):e1007753.  View on PubMed
  15. Valencia K, Erice O, Kostyrko K, Hausmann S, Guruceaga E, Tathireddy A, Flores NM, Sayles LC, Lee AG, Fragoso R, Sun TQ, Vallejo A, Roman M, Entrialgo-Cadierno R, Migueliz I, Razquin N, Fortes P, Lecanda F, Lu J, Ponz-Sarvise M, Chen CZ, Mazur PK, Sweet-Cordero EA, Vicent S. The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas. J Clin Invest. 2020 04 01; 130(4):1879-1895.  View on PubMed
  16. Han K, Pierce SE, Li A, Spees K, Anderson GR, Seoane JA, Lo YH, Dubreuil M, Olivas M, Kamber RA, Wainberg M, Kostyrko K, Kelly MR, Yousefi M, Simpkins SW, Yao D, Lee K, Kuo CJ, Jackson PK, Sweet-Cordero A, Kundaje A, Gentles AJ, Curtis C, Winslow MM, Bassik MC. CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities. Nature. 2020 04; 580(7801):136-141.  View on PubMed
  17. Schott C, Shah AT, Sweet-Cordero EA. Genomic Complexity of Osteosarcoma and Its Implication for Preclinical and Clinical Targeted Therapies. Adv Exp Med Biol. 2020; 1258:1-19.  View on PubMed
  18. Kim JW, Marquez CP, Kostyrko K, Koehne AL, Marini K, Simpson DR, Lee AG, Leung SG, Sayles LC, Shrager J, Ferrer I, Paz-Ares L, Gephart MH, Vicent S, Cochran JR, Sweet-Cordero EA. Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma. Nat Med. 2019 11; 25(11):1783-1795.  View on PubMed
  19. Sanders LM, Rangaswami A, Bjork I, Lam DL, Beale HC, Kephart ET, Durbin A, Learned K, Currie R, Lyle AG, Pfeil J, Shah AT, Lee AG, Leung SG, Behroozfard IH, Breese MR, Peralez J, Hazard FK, Lacayo N, Spunt SL, Haussler D, Salama SR, Sweet-Cordero EA, Vaske OM. Comparative RNA-seq analysis aids in diagnosis of a rare pediatric tumor. Cold Spring Harb Mol Case Stud. 2019 10; 5(5).  View on PubMed
  20. Fernandez KS, Turski ML, Shah AT, Bastian BC, Horvai A, Hardee S, Sweet-Cordero EA. Ewing sarcoma in a child with neurofibromatosis type 1. Cold Spring Harb Mol Case Stud. 2019 10; 5(5).  View on PubMed

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