Joan Garrett

Joan Garrett

Assistant Professor

Assistant Professor

Medical Sciences Building

3207

Pharmacy Garrett Lab - 0514

Professional Summary

The overarching aim of my research program is to better understand signal transduction pathways involved in cancer. I am personally committed to a career in mechanism-based translational research so that I can impact the lives of cancer patients. Our work covers the gamut of basic cancer biology through translational studies in mouse models and human tissues, and interfaces with clinical trials. Our lab uses a variety of technologies including mammalian tissue culture, molecular analyses of gene and protein expression, gene expression microarrays, next-generation DNA sequencing, bioinformatics, protein microarrays, mass spectrometry, mouse models, and live animal imaging.

Education

BA: Ohio University 2002 (Chemistry)

BS: Ohio University 2002 (Computer Science)

PhD: Ohio State University 2007 (Chemistry)

Research and Practice Interests

Mechanisms of mutant HER3 signaling in breast cancer
ERBB3, the gene encoding HER3, is mutated in ~2% of breast cancers and other epithelial cancers. This represents approximately 28,000 patients with newly diagnosed cancers each year in the United States.  HER3 is an important molecule in estrogen receptor (ER)+ breast cancers, which accounts for about 80% of all breast cancers. HER3 mRNA is highest in ER+ or luminal tumors. About 20% of all breast cancers diagnosed are HER2 positive. HER3 is as essential as HER2 for maintaining cell viability in HER2-overexpressing breast cancer cells. Recent studies have found that frequently occurring HER3 mutations in patient tumors promote oncogenic growth in breast and other cell types. Some clinical studies suggest that patients bearing HER3 mutant tumors respond to HER targeted-therapy. We present data that patient-derived HER3 mutations can be activating independent of HER2 over-expression in ER+ breast cancers. In this application, we propose to identify mechanisms by which mutant HER3 promotes breast cancer growth. Next, we will decipher how HER3 mutations cooperate with the estrogen receptor and if HER3 mutations promote evasion from dependence on estrogen signaling. Lastly, we will identify mechanisms of resistance to a HER3 targeted drug in HER3-mutant breast cancers. Molecular profiling of patients’ tumors is becoming commonplace in the clinic, and more patients with HER3-mutant cancers are being identified than ever before. There are currently no approved therapies for this breast cancer subtype. Thus, we aim to identify the most effective treatment options for this population. Since several HER family inhibitors are already approved for use in patients with HER2-amplified breast cancer, these studies have the potential to be rapidly translated to the clinic. Further, these studies will increase our basic understanding of ERBB receptor-driven tumor progression, which can be applied to a larger number of human cancers.



Exploitation of ROS to Abrogate BRAF Inhibitor Resistance in Melanomas
The focus of this research project is to translate a common observation in drug resistant cancers into an exploitable liability for enhanced targeting. Somatic BRAF activating mutations are expressed in ~50% of all melanoma tumors. Clinical development of RAF kinase inhibitors, including vemurafenib and dabrafenib, resulted in a 50% response. Unfortunately all treatments lead to BRAF inhibitor resistant tumors within a year. Reactive oxygen species (ROS) are highly reactive metabolites of oxygen including superoxide, hydrogen peroxide, hydroxyl radical, and hypochlorous acid. It is known that ROS production is induced by BRAF inhibition suggesting BRAF inhibitor induced ROS may play a role in the cellular adaptation to drug treatment. We hypothesize that a ROS-activatable prodrug will extend the efficacy of BRAF inhibitors. We propose to: 1) ROS Status and Mechanism in BRAF Resistant Phenotypes. 2) Extending Dabrafenib Efficacy.

Successful completion of this work will elucidate how BRAF inhibition modulates ROS levels and could identify resistant mechanisms to BRAF inhibitors in melanoma. The results of the in vivo study we propose could lead to clinical trials of BRAF inhibitors in combination with ROS targeted therapy.  This study will have a great impact on future RAF inhibitor clinical trial strategies likely within 5 years and potentially lead to clinical approval for new treatment strategies improving outcomes for those stricken with BRAF mutant melanoma.

 

Positions and Work Experience

2000 -2002 Undergraduate Research Assistant, Ohio University,

2002 -2007 Graduate Student, Chemistry Department, The Ohio State University,

2008 -2013 Postdoctoral Fellow, Hematology-Oncology, Vanderbilt University,

2013 -2014 Research Instructor, Hematology-Oncology, Vanderbilt University,

2015 - Assistant Professor James L. Winkle College of Pharmacy, University of Cincinnati,

Research Support

Grant: #CCR14298180 Investigators:Garrett, Joan 04-11-2015 -04-10-2018 Susan G. Komen Breast Cancer Foundation How breast cancers optimize HER3 signaling to drive therapeutic resistance Role:PI $450,000.00 Active Level:Private Non-Profit

02-29-2016 -02-28-2017 Center for Environmental Genetics The role of ErbB3 in mutant BRAF melanoma Role:PI Completed Type:Grant

07-01-2016 -06-30-2017 Center for Clinical and Translational Science & Training The role of ErbB3 in mutant BRAF melanoma Role:PI Active Type:Grant

Grant: #R40309 Investigators:Garrett, Joan 05-01-2019 -12-31-2020 UC's Collaborative Research Advancement Grants Program - Track 2: Strategic Teams Strategic Collab Grant – Garrett Role:PI $70,000.00 Active Level:Internal UC

Grant: #2019 Sponsored Research Agreement Investigators:Garrett, Joan 05-16-2019 -05-15-2020 Puma Biotechnology, Inc. Identifying mechanisms of HER3 activation and regulation Role:PI $103,781.00 Awarded Level:Industry

Grant: #W81XWH1910441 Investigators:Garrett, Joan; Hodges, Kurt; Merino, Edward 07-01-2019 -06-30-2022 Department of the Army Medical Research Acquisition Activity Targeting PI3K in breast cancer with reactive oxygen species activated scaffold drugs Role:PI $577,800.00 Awarded Level:Federal

Grant: #012461 ISRA_2020 Investigators:Garrett, Joan 01-09-2020 -01-31-2021 Daiichi Sankyo Company, LTD. Mutant HER3 signal transduction in breast cancer Role:PI $104,635.00 Awarded Level:Foreign Industry

Grant: #RSG-20-071-01 - TBG Investigators:Garrett, Joan; Hodges, Kurt 09-01-2020 -08-31-2024 American Cancer Society - Ohio Chapter Mechanisms of mutant HER3 signaling in breast cancer Role:PI $792,000.00 Awarded Level:Private Non-Profit

Publications

Peer Reviewed Publications

Yuan, Long; Mishra, Rosalin; Patel, Hima; Abdulsalam, Safnas; Greis, Kenneth D; Kadekaro, Ana Luisa; Merino, Edward J; Garrett, Joan T (2018. ) Utilization of Reactive Oxygen Species Targeted Therapy to Prolong the Efficacy of BRAF Inhibitors in Melanoma.Journal of Cancer, , 9 (24 ) ,4665-4676 More Information

Mishra, Rosalin; Alanazi, Samar; Yuan, Long; Solomon, Thomas; Thaker, Tarjani M; Jura, Natalia; Garrett, Joan T (2018. ) Activating HER3 mutations in breast cancer.Oncotarget, , 9 (45 ) ,27773-27788 More Information

Mishra, Rosalin; Patel, Hima; Alanazi, Samar; Yuan, Long; Garrett, Joan T (2018. ) HER3 signaling and targeted therapy in cancer.Oncology reviews, , 12 (1 ) ,355 More Information

Mishra, Rosalin; Hanker, Ariella B; Garrett, Joan T (2017. ) Genomic alterations of ERBB receptors in cancer: clinical implications.Oncotarget, , 8 (69 ) ,114371-114392 More Information

Allen, Stephanie D; Garrett, Joan T; Rawale, Sharad V; Jones, Audra L; Phillips, Gary; Forni, Guido; Morris, John C; Oshima, Robert G; Kaumaya, Pravin T P (2007. ) Peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo.Journal of immunology (Baltimore, Md. : 1950), , 179 (1 ) ,472-82 More Information

Garrett, Joan T; Rawale, Sharad; Allen, Stephanie D; Phillips, Gary; Forni, Guido; Morris, John C; Kaumaya, Pravin T P (2007. ) Novel engineered trastuzumab conformational epitopes demonstrate in vitro and in vivo antitumor properties against HER-2/neu.Journal of immunology (Baltimore, Md. : 1950), , 178 (11 ) ,7120-31 More Information

Mishra, Rosalin; Patel, Hima; Alanazi, Samar; Kilroy, Mary Kate; Garrett, Joan T (2021. ) PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects.International journal of molecular sciences, , 22 (7 ) , More Information

Hanker, Ariella B; Garrett, Joan T; Estrada, Mónica Valeria; Moore, Preston D; Ericsson, Paula González; Koch, James P; Langley, Emma; Singh, Sharat; Kim, Phillip S; Frampton, Garrett M; Sanford, Eric; Owens, Philip; Becker, Jennifer; Groseclose, M Reid; Castellino, Stephen; Joensuu, Heikki; Huober, Jens; Brase, Jan C; Majjaj, Samira; Brohée, Sylvain; Venet, David; Brown, David; Baselga, José; Piccart, Martine; Sotiriou, Christos; Arteaga, Carlos L (2017. ) HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2.Clinical cancer research : an official journal of the American Association for Cancer Research, , 23 (15 ) ,4323-4334 More Information

Mishra, Rosalin; Yuan, Long; Patel, Hima; Karve, Aniruddha S; Zhu, Haizhou; White, Aaron; Alanazi, Samar; Desai, Pankaj; Merino, Edward J; Garrett, Joan T (2021. ) Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth.International journal of molecular sciences, , 22 (4 ) , More Information

Garner, Andrew P; Bialucha, Carl U; Sprague, Elizabeth R; Garrett, Joan T; Sheng, Qing; Li, Sharon; Sineshchekova, Olga; Saxena, Parmita; Sutton, Cammie R; Chen, Dongshu; Chen, Yan; Wang, Huiqin; Liang, Jinsheng; Das, Rita; Mosher, Rebecca; Gu, Jian; Huang, Alan; Haubst, Nicole; Zehetmeier, Carolin; Haberl, Manuela; Elis, Winfried; Kunz, Christian; Heidt, Analeah B; Herlihy, Kara; Murtie, Joshua; Schuller, Alwin; Arteaga, Carlos L; Sellers, William R; Ettenberg, Seth A (2013. ) An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin.Cancer research, , 73 (19 ) ,6024-35 More Information

Yuan, Long; Mishra, Rosalin; Patel, Hima; Alanazi, Samar; Wei, Xin; Ma, Zhijun; Garrett, Joan T (2020. ) BRAF Mutant Melanoma Adjusts to BRAF/MEK Inhibitors via Dependence on Increased Antioxidant SOD2 and Increased Reactive Oxygen Species Levels.Cancers, , 12 (6 ) , More Information

Garrett, Joan T; Sutton, Cammie R; Kurupi, Richard; Bialucha, Carl Uli; Ettenberg, Seth A; Collins, Scott D; Sheng, Qing; Wallweber, Jerry; Defazio-Eli, Lisa; Arteaga, Carlos L (2013. ) Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110? inhibitor potently blocks PI3K signaling and growth of HER2+ breast cancers.Cancer research, , 73 (19 ) ,6013-23 More Information

Patel, Hima; Yacoub, Nour; Mishra, Rosalin; White, Aaron; Long, Yuan; Alanazi, Samar; Garrett, Joan T (2020. ) Current Advances in the Treatment of BRAF-Mutant Melanoma.Cancers, , 12 (2 ) , More Information

Garrett, Joan T; Sutton, Cammie R; Kuba, María Gabriela; Cook, Rebecca S; Arteaga, Carlos L (2013. ) Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function.Clinical cancer research : an official journal of the American Association for Cancer Research, , 19 (3 ) ,610-9 More Information

Zhu, Haizhou; Mishra, Rosalin; Yuan, Long; Abdul Salam, Safnas F; Liu, Jing; Gray, George; Sterling, Alyssa D; Wunderlich, Mark; Landero-Figueroa, Julio; Garrett, Joan T; Merino, Edward J (2019. ) Oxidative Cyclization-Induced Activation of a Phosphoinositide 3-Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics.ChemMedChem, , 14 (22 ) ,1933-1939 More Information

Garrett, Joan T; Chakrabarty, Anindita; Arteaga, Carlos L (2011. ) Will PI3K pathway inhibitors be effective as single agents in patients with cancer?.Oncotarget, , 2 (12 ) ,1314-21 More Information

Cook, Rebecca S; Garrett, Joan T; Sánchez, Violeta; Stanford, Jamie C; Young, Christian; Chakrabarty, Anindita; Rinehart, Cammie; Zhang, Yixian; Wu, Yaming; Greenberger, Lee; Horak, Ivan D; Arteaga, Carlos L (2011. ) ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis.Cancer research, , 71 (11 ) ,3941-51 More Information

Garrett, Joan T; Arteaga, Carlos L (2011. ) Resistance to HER2-directed antibodies and tyrosine kinase inhibitors: mechanisms and clinical implications.Cancer biology & therapy, , 11 (9 ) ,793-800 More Information

Garrett, Joan T; Olivares, María Graciela; Rinehart, Cammie; Granja-Ingram, Nara D; Sánchez, Violeta; Chakrabarty, Anindita; Dave, Bhuvanesh; Cook, Rebecca S; Pao, William; McKinely, Eliot; Manning, H C; Chang, Jenny; Arteaga, Carlos L (2011. ) Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase.Proceedings of the National Academy of Sciences of the United States of America, , 108 (12 ) ,5021-6 More Information

Miller, Todd W; Rexer, Brent N; Garrett, Joan T; Arteaga, Carlos L (2011. ) Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer.Breast cancer research : BCR, , 13 (6 ) ,224 More Information

Schwarz, Luis J; Fox, Emily M; Balko, Justin M; Garrett, Joan T; Kuba, María Gabriela; Estrada, Mónica Valeria; González-Angulo, Ana María; Mills, Gordon B; Red-Brewer, Monica; Mayer, Ingrid A; Abramson, Vandana; Rizzo, Monica; Kelley, Mark C; Meszoely, Ingrid M; Arteaga, Carlos L (2014. ) LYN-activating mutations mediate antiestrogen resistance in estrogen receptor-positive breast cancer.The Journal of clinical investigation, , 124 (12 ) ,5490-502 More Information

Kaumaya, Pravin T P; Foy, Kevin Chu; Garrett, Joan; Rawale, Sharad V; Vicari, Daniele; Thurmond, Jennifer M; Lamb, Tammy; Mani, Aruna; Kane, Yahaira; Balint, Catherine R; Chalupa, Donald; Otterson, Gregory A; Shapiro, Charles L; Fowler, Jeffrey M; Grever, Michael R; Bekaii-Saab, Tanios S; Carson, William E (2009. ) Phase I active immunotherapy with combination of two chimeric, human epidermal growth factor receptor 2, B-cell epitopes fused to a promiscuous T-cell epitope in patients with metastatic and/or recurrent solid tumors.Journal of clinical oncology : official journal of the American Society of Clinical Oncology, , 27 (31 ) ,5270-7 More Information

Dakappagari, Naveen K; Lute, Kenneth D; Rawale, Sharad; Steele, Joan T; Allen, Stephanie D; Phillips, Gary; Reilly, R Todd; Kaumaya, Pravin T P (2005. ) Conformational HER-2/neu B-cell epitope peptide vaccine designed to incorporate two native disulfide bonds enhances tumor cell binding and antitumor activities.The Journal of biological chemistry, , 280 (1 ) ,54-63 More Information

Book Chapter

Steele, J.T., Rawale, S., Kaumaya, P.T.P. (2005 ) Cancer Immunotherapy with Rationally Designed Synthetic Peptides Handbook of Biologically Active Peptides .(pp. 511).Elsevier

Honors and Awards

2000 Teaching Assistant Training and Research Fellowship- Ohio University

2001 Pfizer Undergraduate Fellowship

2001 Phi Beta Kappa

2002 Graduated from Ohio University Magna Cum Laude

2002 -2003 University Fellowship- The Ohio State University

2003 -2005 Chemistry-Biology Interface Training Program T32 NIH Grant- The Ohio State University

2008 -2010 Molecular Endocrinology Training Program T32 NIH Grant- Vanderbilt University

2009 Accepted participant in the AACR Pathobiology of Cancer Workshop

2009 San Antonio Breast Cancer Symposium Basic Science Scholars Scholarship

2010 F32 NIH Grant- Postdoctoral Fellowship (declined due to overlapping award)

2010 -2013 Postdoctoral Fellowship Department of Defense Breast Cancer Research Program

2010 -2013 Postdoctoral Fellowship American Cancer Society

2011 American Association for Cancer Research Scholar-in-Training Travel Award

2011 Research Acceleration Grant (In Kind) for the American Cancer Society

2012 AACR-Women in Cancer Research Scholar Travel Award

2012 Vanderbilt Ingram Cancer Center Poster Award

2012 Benjamin F. Trump Award and Aspen Cancer Conference Fellow

2013 AACR-Women in Cancer Research Scholar Travel Award

2016 Susan G. Komen Jon Shevell Young Scientist Travel Scholarship

Keywords

signal transduction, breast cancer, melanoma, resistance to targeted therapy

Contact Information

joan.garrett@uc.edu

Research - Garrett's Lab
231 Albert Sabin Way
Cincinnati  Ohio, 45229
Phone: 513-558-6662
http://pharmacy.uc.edu/garrett