University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Alejandro Sweet-Cordero, MD

Alejandro Sweet-Cordero, MD

Associate Professor of Pediatrics, UCSF
Director, Molecular Oncology Initiative, UCSF Helen Diller Family Comprehensive Cancer Center
Benioff UCSF Professorship in Children's Health

Cancer Center Program Memberships

Pediatric Malignancies

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.

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, we are carrying out translational studies to evaluate the use of targeted therapies for this disease. Our sarcoma work is facilitated by access to a large (n>30) collection of patient-derived xenograft models. 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. 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.

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


Professional Experience

  • 1998 – 1999
    Clinical Instructor, Department of Pediatrics. University of California San Francisco
  • 2000 - 2002
  • Research Fellow, Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
  • 2002-2005
    Clinical Instructor, Pediatric Hematology-Oncology, Children's Hospital/Dana-Farber Cancer Institute, Boston, MA
  • 2005-2012
    Assistant Professor of Pediatrics, Stanford University School of Medicine
  • 2013-2016
    Associate Professor of Pediatrics, Stanford University School of Medicine
  • 2017- present
    Associate Professor of Pediatrics, University of California San Francisco

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. 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 Nov; 25(11):1783-1795.
    View on PubMed
  2. 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 Oct; 5(5).
    View on PubMed
  3. 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 Oct; 5(5).
    View on PubMed
  4. Vaske OM, Bjork I, Salama SR, Beale H, Tayi Shah A, Sanders L, Pfeil J, Lam DL, Learned K, Durbin A, Kephart ET, Currie R, Newton Y, Swatloski T, McColl D, Vivian J, Zhu J, Lee AG, Leung SG, Spillinger A, Liu HY, Liang WS, Byron SA, Berens ME, Resnick AC, Lacayo N, Spunt SL, Rangaswami A, Huynh V, Torno L, Plant A, Kirov I, Zabokrtsky KB, Rassekh SR, Deyell RJ, Laskin J, Marra MA, Sender LS, Mueller S, Sweet-Cordero EA, Goldstein TC, Haussler D. Comparative Tumor RNA Sequencing Analysis for Difficult-to-Treat Pediatric and Young Adult Patients With Cancer. JAMA Netw Open. 2019 Oct 02; 2(10):e1913968.
    View on PubMed
  5. Chao AK, Meyer JA, Lee AG, Hecht A, Tarver T, Van Ziffle J, Koegel AK, Golden C, Braun BS, Sweet-Cordero EA, Smith CC, Dvorak CC, Loh ML, Stieglitz E. Fusion driven JMML: a novel CCDC88C-FLT3 fusion responsive to sorafenib identified by RNA sequencing. Leukemia. 2019 Sep 12.
    View on PubMed
  6. Roberts RD, Lizardo MM, Reed DR, Hingorani P, Glover J, Allen-Rhoades W, Fan T, Khanna C, Sweet-Cordero EA, Cash T, Bishop MW, Hegde M, Sertil AR, Koelsche C, Mirabello L, Malkin D, Sorensen PH, Meltzer PS, Janeway KA, Gorlick R, Crompton BD. Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group. Cancer. 2019 Oct 15; 125(20):3514-3525.
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  7. Ren Y, Huang S, Dai C, Xie D, Zheng L, Xie H, Zheng H, She Y, Zhou F, Wang Y, Li P, Fei K, Jiang G, Zhang Y, Su B, Sweet-Cordero EA, Tran NL, Yang Y, Patel JN, Rolfo C, Rocco G, Cardona AF, Tuzi A, Suter MB, Yang P, Xu W, Chen C. Germline Predisposition and Copy Number Alteration in Pre-stage Lung Adenocarcinomas Presenting as Ground-Glass Nodules. Front Oncol. 2019; 9:288.
    View on PubMed
  8. Sweet-Cordero EA, Biegel JA. The genomic landscape of pediatric cancers: Implications for diagnosis and treatment. Science. 2019 03 15; 363(6432):1170-1175.
    View on PubMed
  9. Sayles LC, Breese MR, Koehne AL, Leung SG, Lee AG, Liu HY, Spillinger A, Shah AT, Tanasa B, Straessler K, Hazard FK, Spunt SL, Marina N, Kim GE, Cho SJ, Avedian RS, Mohler DG, Kim MO, DuBois SG, Hawkins DS, Sweet-Cordero EA. Genome-Informed Targeted Therapy for Osteosarcoma. Cancer Discov. 2019 01; 9(1):46-63.
    View on PubMed
  10. Marini KD, Croucher DR, McCloy RA, Vaghjiani V, Gonzalez-Rajal A, Hastings JF, Chin V, Szczepny A, Kostyrko K, Marquez C, Jayasekara WSN, Alamgeer M, Boolell V, Han JZR, Waugh T, Lee HC, Oakes SR, Kumar B, Harrison CA, Hedger MP, Lorensuhewa N, Kita B, Barrow R, Robinson BW, de Kretser DM, Wu J, Ganju V, Sweet-Cordero EA, Burgess A, Martelotto LG, Rossello FJ, Cain JE, Watkins DN. Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy. Sci Transl Med. 2018 07 25; 10(451).
    View on PubMed
  11. Gwinn DM, Lee AG, Briones-Martin-Del-Campo M, Conn CS, Simpson DR, Scott AI, Le A, Cowan TM, Ruggero D, Sweet-Cordero EA. Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase. Cancer Cell. 2018 01 08; 33(1):91-107.e6.
    View on PubMed
  12. Hsieh G, Bierman R, Szabo L, Lee AG, Freeman DE, Watson N, Sweet-Cordero EA, Salzman J. Statistical algorithms improve accuracy of gene fusion detection. Nucleic Acids Res. 2017 Jul 27; 45(13):e126.
    View on PubMed
  13. Alvarez E, Seppa M, Rivas S, Fuentes L, Valverde P, Antillón-Klussmann F, Castellanos M, Sweet-Cordero EA, Messacar K, Kurap J, Bustamante M, Howard SC, Efron B, Luna-Fineman S. Improvement in treatment abandonment in pediatric patients with cancer in Guatemala. Pediatr Blood Cancer. 2017 Oct; 64(10).
    View on PubMed
  14. Vallejo A, Perurena N, Guruceaga E, Mazur PK, Martinez-Canarias S, Zandueta C, Valencia K, Arricibita A, Gwinn D, Sayles LC, Chuang CH, Guembe L, Bailey P, Chang DK, Biankin A, Ponz-Sarvise M, Andersen JB, Khatri P, Bozec A, Sweet-Cordero EA, Sage J, Lecanda F, Vicent S. An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer. Nat Commun. 2017 02 21; 8:14294.
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  15. Chuang CH, Greenside PG, Rogers ZN, Brady JJ, Yang D, Ma RK, Caswell DR, Chiou SH, Winters AF, Grüner BM, Ramaswami G, Spencley AL, Kopecky KE, Sayles LC, Sweet-Cordero EA, Li JB, Kundaje A, Winslow MM. Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat Med. 2017 Mar; 23(3):291-300.
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  16. Brady JJ, Chuang CH, Greenside PG, Rogers ZN, Murray CW, Caswell DR, Hartmann U, Connolly AJ, Sweet-Cordero EA, Kundaje A, Winslow MM. An Arntl2-Driven Secretome Enables Lung Adenocarcinoma Metastatic Self-Sufficiency. Cancer Cell. 2016 05 09; 29(5):697-710.
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  17. Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sánchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noël PB, Braren R, Erkan M, Kleeff J, Sipos B, Sayles LC, Heikenwalder M, Heßmann E, Ellenrieder V, Esposito I, Jacks T, Bradner JE, Khatri P, Sweet-Cordero EA, Attardi LD, Schmid RM, Schneider G, Sage J, Siveke JT. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med. 2015 Oct; 21(10):1163-71.
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  18. Marques Howarth M, Simpson D, Ngok SP, Nieves B, Chen R, Siprashvili Z, Vaka D, Breese MR, Crompton BD, Alexe G, Hawkins DS, Jacobson D, Brunner AL, West R, Mora J, Stegmaier K, Khavari P, Sweet-Cordero EA. Long noncoding RNA EWSAT1-mediated gene repression facilitates Ewing sarcoma oncogenesis. J Clin Invest. 2014 Dec; 124(12):5275-90.
    View on PubMed
  19. Chen R, Khatri P, Mazur PK, Polin M, Zheng Y, Vaka D, Hoang CD, Shrager J, Xu Y, Vicent S, Butte AJ, Sweet-Cordero EA. A meta-analysis of lung cancer gene expression identifies PTK7 as a survival gene in lung adenocarcinoma. Cancer Res. 2014 May 15; 74(10):2892-902.
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  20. Valdmanis PN, Roy-Chaudhuri B, Kim HK, Sayles LC, Zheng Y, Chuang CH, Caswell DR, Chu K, Zhang Y, Winslow MM, Sweet-Cordero EA, Kay MA. Upregulation of the microRNA cluster at the Dlk1-Dio3 locus in lung adenocarcinoma. Oncogene. 2015 Jan 02; 34(1):94-103.
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