Justin M. Balko, Pharm.D., Ph.D.
Research Assistant Professor of Medicine (Hematology/Oncology)
Vanderbilt University Medical Center
777 Preston Research Building
Nashville, TN 37232-6307
- Pharm.D., State University of New York at Buffalo
- Ph.D., University of Kentucky, Department of Pharmaceutical Sciences
Translational cancer research
Our laboratory is focused on improving treatment oucomes in breast cancer (particularly triple-negative breast cancer) as well as in other solid tumors. Our approach is to integrate data from genomic and molecular profiling studies with molecular biology and signal transduction methodologies to translationally identify altered pathways in cancer, the functional consequences of these alterations, and ways to directly target them in patients to improve clinical outcomes and survival. These efforts span in silico (publically available databases), in vitro (cell culture), in vivo (mouse and human clinical studies) and in situ (histology) methods.
We are currently exploring ways of targeting drug-resistant tumor cells which persist after neoadjuvant chemotherapy (NAC). NAC is used increasingly in patients with triple-negative breast cancer (TNBC), which does not express estrogen receptor, progesterone receptor or human epidermal growth factor-2 (HER2) amplification. The purpose of NAC is to increase the patient¿¿¿s chances of undergoing breast-conserving surgery and to eliminate clinically silent micro-metastases. When employed, NAC results in pathological complete response (pCR) in about 30% of TNBC patients. These patients have a favorable recurrence-free and overall survival. The remaining patients with residual viable cancer in the breast or lymph nodes exhibit high rates of metastatic recurrence and an overall poor long term outcome.
Importantly, there are no approved therapies for use in TNBC patients with residual disease at surgery following NAC. For these patients, the standard of care is watchful waiting. In light of this, we performed molecular profiling of the residual disease from such patients in order to identify clinically actionable alterations that could be exploited therapeutically to reduce recurrence and mortality. From these studies, we have identified loss of dual specificity phosphatase 4 (DUSP4) in a significant percentage of post-NAC TNBCs (Balko et al, Nature Medicine, 2012) . DUSP4 is a phosphatase which negatively regulates the MEK and JNK signaling pathways and is a potential tumor suppressor. We have recently shown that DUSP4 regulates cancer stem cell-like phenotypes and chemotherapeutic resistance (Balko et al, Cancer Research, 2013). Furthermore, our mechanistic studies suggest that DUSP4-deficient breast tumor models are targetable by inhibitors of MEK or ERK.
We have also recently used targeted next-generation sequencing to characterize the spectrum of tumor-genome lesions in a series of 74 post-NAC TNBCs and have detected several potentially actionable molecular alterations (Balko et al, Cancer Discovery, 2014). Importantly, several of these alterations (including amplification of MCL1, JAK2, and loss of PTEN) are enriched in residual drug-resistant tumors after chemotherapy compared to primary untreated tumors. These data suggest additional actionable molecular targets which could be exploited in the adjuvant setting to reduce recurrence and improve survival of this devastating disease, and validation of these concepts will also be a continuing focus of the laboratory.
- Jeselsohn, R, Yelensky, R, Buchwalter, G, Frampton, G, Meric-Bernstam, F, Gonzalez-Angulo, AM, Ferrer-Lozano, J, Perez-Fidalgo, JA, Cristofanilli, M, G¿¿mez, H, Arteaga, CL, Giltnane, J, Balko, JM, Cronin, MT, Jarosz, M, Sun, J, Hawryluk, M, Lipson, D, Otto, G, Ross, JS, Dvir, A, Soussan-Gutman, L, Wolf, I, Rubinek, T, Gilmore, L, Schnitt, S, Come, SE, Pusztai, L, Stephens, P, Brown, M, Miller, VA Emergence of constitutively active estrogen receptor-¿¿ mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res, 20(7), 1757-67, 2014.
- Johnson, DB, Dahlman, KH, Knol, J, Gilbert, J, Puzanov, I, Means-Powell, J, Balko, JM, Lovly, CM, Murphy, BA, Goff, LW, Abramson, VG, Crispens, MA, Mayer, IA, Berlin, JD, Horn, L, Keedy, VL, Reddy, NM, Arteaga, CL, Sosman, JA, Pao, W Enabling a genetically informed approach to cancer medicine: a retrospective evaluation of the impact of comprehensive tumor profiling using a targeted next-generation sequencing panel. Oncologist, 19(6), 616-22, 2014.
- Balko, JM, Giltnane, JM, Wang, K, Schwarz, LJ, Young, CD, Cook, RS, Owens, P, Sanders, ME, Kuba, MG, S¿¿nchez, V, Kurupi, R, Moore, PD, Pinto, JA, Doimi, FD, G¿¿mez, H, Horiuchi, D, Goga, A, Lehmann, BD, Bauer, JA, Pietenpol, JA, Ross, JS, Palmer, GA, Yelensky, R, Cronin, M, Miller, VA, Stephens, PJ, Arteaga, CL Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov, 4(2), 232-45, 2014.
- Giltnane, JM, Balko, JM Rationale for targeting the Ras/MAPK pathway in triple-negative breast cancer. Discov Med, 17(95), 275-83, 2014.
- Mayer, IA, Abramson, VG, Isakoff, SJ, Forero, A, Balko, JM, Kuba, MG, Sanders, ME, Yap, JT, Van den Abbeele, AD, Li, Y, Cantley, LC, Winer, E, Arteaga, CL Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol, 32(12), 1202-9, 2014.
- Balko, JM, Schwarz, LJ, Bhola, NE, Kurupi, R, Owens, P, Miller, TW, G¿¿mez, H, Cook, RS, Arteaga, CL Activation of MAPK pathways due to DUSP4 loss promotes cancer stem cell-like phenotypes in basal-like breast cancer. Cancer Res, 73(20), 6346-58, 2013.
- Young, CD, Pfefferle, AD, Owens, P, Kuba, MG, Rexer, BN, Balko, JM, S¿¿nchez, V, Cheng, H, Perou, CM, Zhao, JJ, Cook, RS, Arteaga, CL Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression or signaling. Cancer Res, 2013.
- Morrison, MM, Hutchinson, K, Williams, MM, Stanford, JC, Balko, JM, Young, C, Kuba, MG, S¿¿nchez, V, Williams, AJ, Hicks, DJ, Arteaga, CL, Prat, A, Perou, CM, Earp, HS, Massarweh, S, Cook, RS ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. J Clin Invest, 123(10), 4329-43, 2013.
- Dennison, JB, Molina, JR, Mitra, S, Gonz¿¿lez-Angulo, AM, Balko, JM, Kuba, MG, Sanders, ME, Pinto, JA, G¿¿mez, HL, Arteaga, CL, Brown, RE, Mills, GB Lactate dehydrogenase B: a metabolic marker of response to neoadjuvant chemotherapy in breast cancer. Clin Cancer Res, 19(13), 3703-13, 2013.
- Hanker, AB, Pfefferle, AD, Balko, JM, Kuba, MG, Young, CD, S¿¿nchez, V, Sutton, CR, Cheng, H, Perou, CM, Zhao, JJ, Cook, RS, Arteaga, CL Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. Proc Natl Acad Sci U S A, 110(35), 14372-7, 2013.
- Bhola, NE, Balko, JM, Dugger, TC, Kuba, MG, S¿¿nchez, V, Sanders, M, Stanford, J, Cook, RS, Arteaga, CL TGF-¿¿ inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest, 123(3), 1348-58, 2013.
- Balko, JM, Stricker, TP, Arteaga, CL The genomic map of breast cancer: which roads lead to better targeted therapies. Breast Cancer Res, 15(4), 209, 2013.
- Bryant, JL, Britson, J, Balko, JM, Willian, M, Timmons, R, Frolov, A, Black, EP A microRNA gene expression signature predicts response to erlotinib in epithelial cancer cell lines and targets EMT. Br J Cancer, 106(1), 148-56, 2012.
- Balko, JM, Mayer, IA, Sanders, ME, Miller, TW, Kuba, MG, Meszoely, IM, Wagle, N, Garraway, LA, Arteaga, CL Discordant cellular response to presurgical letrozole in bilateral synchronous ER+ breast cancers with a KRAS mutation or FGFR1 gene amplification. Mol Cancer Ther, 11(10), 2301-5, 2012.
- Balko, JM, Arteaga, CL Molecular signatures of lung cancer: defining new diagnostic and therapeutic paradigms. Mol Diagn Ther, 16(1), 1-6, 2012.
- Oh, YT, Yue, P, Zhou, W, Balko, JM, Black, EP, Owonikoko, TK, Khuri, FR, Sun, SY Oncogenic Ras and B-Raf proteins positively regulate death receptor 5 expression through co-activation of ERK and JNK signaling. J Biol Chem, 287(1), 257-67, 2012.
- Balko, JM, Cook, RS, Vaught, DB, Kuba, MG, Miller, TW, Bhola, NE, Sanders, ME, Granja-Ingram, NM, Smith, JJ, Meszoely, IM, Salter, J, Dowsett, M, Stemke-Hale, K, Gonz¿¿lez-Angulo, AM, Mills, GB, Pinto, JA, G¿¿mez, HL, Arteaga, CL Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat Med, 18(7), 1052-9, 2012.
- Balko, JM, Miller, TW, Morrison, MM, Hutchinson, K, Young, C, Rinehart, C, S¿¿nchez, V, Jee, D, Polyak, K, Prat, A, Perou, CM, Arteaga, CL, Cook, RS The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium. Proc Natl Acad Sci U S A, 109(1), 221-6, 2012.
- Miller, TW, Balko, JM, Ghazoui, Z, Dunbier, A, Anderson, H, Dowsett, M, Gonz¿¿lez-Angulo, AM, Mills, GB, Miller, WR, Wu, H, Shyr, Y, Arteaga, CL A gene expression signature from human breast cancer cells with acquired hormone independence identifies MYC as a mediator of antiestrogen resistance. Clin Cancer Res, 17(7), 2024-34, 2011.
- Fox, EM, Miller, TW, Balko, JM, Kuba, MG, S¿¿nchez, V, Smith, RA, Liu, S, Gonz¿¿lez-Angulo, AM, Mills, GB, Ye, F, Shyr, Y, Manning, HC, Buck, E, Arteaga, CL A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer. Cancer Res, 71(21), 6773-84, 2011.
- Balko, JM, Arteaga, CL Dead-box or black-box: is DDX1 a potential biomarker in breast cancer. Breast Cancer Res Treat, 127(1), 65-7, 2011.
- Balko, JM, Black, EP Do the genes tell us the path of most resistance. Cancer Biol Ther, 11(2), 213-5, 2011.
- Miller, TW, Balko, JM, Fox, EM, Ghazoui, Z, Dunbier, A, Anderson, H, Dowsett, M, Jiang, A, Smith, RA, Maira, SM, Manning, HC, Gonz¿¿lez-Angulo, AM, Mills, GB, Higham, C, Chanthaphaychith, S, Kuba, MG, Miller, WR, Shyr, Y, Arteaga, CL ER¿¿-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov, 1(4), 338-51, 2011.
- Miller, TW, Balko, JM, Arteaga, CL Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol, 29(33), 4452-61, 2011.
- Ghosh, R, Narasanna, A, Wang, SE, Liu, S, Chakrabarty, A, Balko, JM, Gonz¿¿lez-Angulo, AM, Mills, GB, Penuel, E, Winslow, J, Sperinde, J, Dua, R, Pidaparthi, S, Mukherjee, A, Leitzel, K, Kostler, WJ, Lipton, A, Bates, M, Arteaga, CL Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers. Cancer Res, 71(5), 1871-82, 2011.