A. Ari Hakimi: Research Overview

A. Ari Hakimi: Research Overview


Contribution to Science

1. Kidney Cancer Metabolism

Renal cell carcinomas are defined as much by their altered metabolism as by their unique genomics. My collaborative work on metabolic changes associated with disease progression in clear cell RCC resulted in a landmark paper on the metabolic landscape of this disease (Cancer Cell 2016). We then had a series of papers that addressed the “obesity paradox”: obese individuals have higher incidence of RCC, but lower disease-specific mortality. We demonstrated that ccRCC in obese patients has lower gene and protein expression of fatty acid synthase (FASN), which correlated with improved outcomes. We recently demonstrated that obese patient have a unique tumor microenvironment, which may explain their improved outcomes after either anti-VEGF therapy or immunotherapies.

Hakimi AA, Furberg H, Zabor EC, Jacobsen A, Schultz N, Ciriello G, Mikklineni N, Fiegoli B, Kim PH, Voss MH, Shen H, Laird PW, Sander C, Reuter VE, Motzer RJ, Hsieh JJ, Russo P. An epidemiologic and genomic investigation into the obesity paradox in renal cell carcinoma. J Natl Cancer Inst. 2013;105(24):1862-70. PMC3866155.

Hakimi AA, Reznik E, Lee CH, Creighton CJ, Brannon AR, Luna A, Aksoy BA, Liu EM, Shen R, Lee W, Chen Y, Stirdivant SM, Russo P, Chen YB, Tickoo SK, Reuter VE, Cheng EH, Sander C, Hsieh JJ. An integrated metabolic atlas of clear cell renal cell carcinoma. Cancer Cell. 2016; 29(1):104-116. PMC4809063.

Sanchez A, Furberg H, Kuo F, Vuong L, Ged Y, Patil S, Ostrovnaya I, Petruzella S, Reising A, Patel P, Mano R, Coleman J, Russo P, Liu CH, Dannenberg AJ, Chan TA, Motzer R, Voss MH, Hakimi AA. Transcriptomic signatures related to the obesity paradox in patients with clear cell renal cell carcinoma: a cohort study. Lancet Oncol. 2020; 21(2):283-293. PMC7082892.

Tang C, Xie AX, Liu EM, Kuo F, Kim M, DiNatale RG, Golkaram M, Chen YB, Gupta S, Motzer RJ, Russo P, Coleman J, Carlo MI, Voss MH, Kotecha RR, Lee CH, Tansey W, Schultz N, Hakimi AA*, Reznik E. mmunometabolic coevolution defines unique microenvironmental niches in ccRCC. Cell Metabolism. 2023 Jun 28:S1550-4131(23)00215-2. PMID 37413991 (*co–senior author).

2. Kidney Cancer Immunity

Immune infiltration patterns differ greatly across cancer types. To learn why, I have investigated the genomic mechanisms for these distinct patterns. I published a critical pan-cancer analysis showing that ccRCC is among the most immune-infiltrated solid tumors, a finding that has direct implications for immunotherapeutic strategies. Applying techniques developed in this pan-cancer analysis, my group demonstrated that in ccRCC, immune factors in the tumor microenvironment, along with angiogenic factors, are associated with response to tyrosine kinase inhibitor therapy. These finding have potential to inform the personalization of therapy. I am currently leading additional genomics analyses of large immunotherapy trials in RCC and we have recently developed immunocompetent, genetically faithful, ccRCC mouse models to mechanistically interrogate therapeutic responses.

Hakimi AA, Voss MD, Kuo F, Sanchez A, Liu M, Nixon BG, Vuong L, Ostrovnaya I, Chen YB, Reuter V, Riaz N, Cheng Y, Patel P, Marker M, Reising A, Li MO, Chan TA, Motzer R. Transcriptomic profiling of the tumor microenvironment reveals distinct subgroups of clear cell renal cell cancer - data from a randomized Phase III trial. Cancer Discov. 2019;9(4):510-525. PMC6697163.

Krishna C, DiNatale RG, Kuo F, Srivastava RM, Vuong L, Chowell D, Gupta S, Vanderbilt C, Purohit TA, Liu M, Kansler E, Nixon BG, Chen YB, Makarov V, Blum KA, Attalla K, Weng S, Salmans ML, Golkaram M, Liu L, Zhang S, Vijayaraghavan R, Pawlowski T, Reuter V, Carlo MI, Voss MH, Coleman J, Russo P, Motzer RJ, Li MO, Leslie CS, Chan TA, Hakimi AA. Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy. Cancer Cell 2021, 39(5): 662-677. PMC8268947.

Kansler ER, Dadi S, Krishna C, Nixon BG, Stamatiades EG, Liu M, Kuo F, Zhang J, Zhang X, Capistrano K, Blum KA, Weiss K, Kedl RM, Cui G, Ikuta K, Chan TA, Leslie CS, Hakimi AA*, Li MO. Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies. Nat Immunol. 2022. PMID: 35618834 (*co–senior author).

Rappold PM, Vuong L, Leibold J, Chakiryan NH, Curry M, Kuo F, Sabio E, Jiang H, Nixon BG, Liu M, Berglund AE, Silagy AW, Mascareno A, Golkaram M, Marker M, Reising A, Savchenko A, Millholland JM, Chen YB, Russo P, Coleman J, Reznik E, Manley BJ, Ostrovnaya I, Makarov V, DiNatale RG, Blum KA, Ma X, Chowell D, Li MO, Solit DB, Lowe SW, Chan TA, Motzer RJ, Voss MH, Hakimi AA. A Targetable Myeloid Inflammatory State Governs Disease Recurrence in Clear Cell Renal Cell Carcinoma. Cancer Discov. 2022 Jun 27:candisc.0925.2021. doi: 10.1158/2159-8290.CD-21-0925. Epub ahead of print. PMID: 35758895.

3. Kidney Cancer Biomarkers

My work has elucidated several critical biomarkers in clear cell RCC. Our group was the first to demonstrate that mutations in BAP1 and SETD2 are associated with adverse outcomes in localized clear cell RCC, resulting in a highly cited paper in Clinical Cancer Research. We also demonstrated associations between mutational biomarkers and long-term response to mTOR inhibitors. Moreover, we showed that tumor heterogeneity may exist in small tumor masses, and that patients with outstanding response to mTOR inhibitors often have variable susceptibility mutations upstream in the mTOR signaling pathway. I applied genomic analysis to a technical problem: uncertainty over whether RCC cell lines truly resemble the tumor subtypes they are meant to represent. To address this, I led an analysis that compared genomic characteristics of RCC cell lines to those of three renal cancer subtypes. This work provided a guide for selection of appropriate cell lines for RCC research.

Hakimi AA, Ostrovnaya I, Reva B, Schultz N, Chen YB, Gonen M, Liu H, Takeda S, Voss MH, Tickoo SK, Reuter VE, Russo P, Cheng EH, Sander C, Motzer RJ, Hsieh JJ. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin Cancer Res. 2013;19:3259-67. PMC3708609.

Sinha R, Winer AG, Chevinsky M, Jakubowski C, Chen YB, Dong Y, Tickoo SK, Reuter VE, Russo P, Coleman JA, Sander C, Hsieh JJ, Hakimi AA. Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection. Nat Commun. 2017;8:15165. PMC5436135.

Voss MH, Reising A, Cheng Y, Patel P, Marker M, Kuo F, Chan TA, Choueiri TK, Hsieh JJ, Hakimi AA, Motzer RJ. Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study. Lancet Oncol. 2018;19(12):1688-1698. PMC6701184.

Attalla K, DiNatale RG, Rappold PM, Fong CJ, Sanchez-Vega F, Silagy AW, Weng S, Coleman J, Lee CH, Carlo MI, Durack JC, Solomon SB, Reuter VE, Russo P, Chan TA, Motzer RJ, Schultz ND, Reznik E, Voss MH, Hakimi AA. Prevalence and Landscape of Actionable Genomic Alterations in Renal Cell Carcinoma. Clin Cancer Res. 2021 Oct 15;27(20):5595-5606. PMCID: PMC8530915.

4. Kidney Cancer TCGA Projects

I have been involved in all three TCGA marker papers for kidney cancer as well as a recently published meta-analysis of all three RCC subtypes. The data generated in these projects have served as the starting point for numerous subsequent investigations, from our group and others. I continue to participate in and direct collaborative projects. Moreover, I co-founded the clinical kidney cancer TCGA consortium with James Hsieh, MD, PhD, which has led to several high-profile publications.

(Hakimi AA) Cancer Genome Atlas Research Network.Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature.2013;499(7456):43-9. PMC3771322.

Davis CF, Ricketts CJ, Wang M, Yang L, Cherniack AD, Shen H, Buhay C, Kang H, Kim SC, Fahey CC, Hacker KE, Bhanot G, Gordenin DA, Chu A, Gunaratne PH, Biehl M, Seth S, Kaipparettu BA, Bristow CA, Donehower LA, Wallen EM, Smith AB, Tickoo SK, Tamboli P, Reuter V, Schmidt LS, Hsieh JJ, Choueiri TK, Hakimi AA; The Cancer Genome Atlas Research Network, Chin L, Meyerson M, Kucherlapati R, Park WY, Robertson AG, Laird PW, Henske EP, Kwiatkowski DJ, Park PJ, Morgan M, Shuch B, Muzny D, Wheeler DA, Linehan WM, Gibbs RA, Rathmell WK, Creighton CJ. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 2014;26:319-30. PMC4160352.

(Hakimi AA) Cancer Genome Atlas Research Network.Comprehensive molecular characterization of papillary renal-cell carcinoma. New Engl J Med. 2015;374(2):135-45 PMC4775252.

Chen F, Zhang Y, Şenbabaoğlu Y, Ciriello G, Yang L, Reznik E, Shuch B, Micevic G, De Velasco G, Shinbrot E, Noble MS, Lu Y, Covington KR, Xi L, Drummond JA, Muzny D, Kang H, Lee J, Tamboli P, Reuter V, Shelley CS, Kaipparettu BA, Bottaro DP, Godwin AK, Gibbs RA, Getz G, Kucherlapati R, Park PJ, Sander C, Henske EP, Zhou JH, Kwiatkowski DJ, Ho TH, Choueiri TK, Hsieh JJ, Akbani R, Mills GB, Hakimi AA, Wheeler DA, Creighton CJ. Multilevel genomics-based taxonomy of renal cell carcinoma. Cell Rep. 2016;14(10):2476-89. PMC4794376.

5. Kidney Cancer Clinical Projects

I have published numerous clinical and translational papers related to kidney cancer patient outcomes. In this work I supervise clinical and research fellows on projects integrating genomic, clinical, and pathologic features to understand patient-specific outcomes following renal cancer surgeries.

Kashan M, Ghanaat M, Hotker AM, Duzgol C, Sanchez A, DiNatale RG, Blum KA, Becerra MF, Manley BJ, Casuscelli J, Chiok M, Coleman JA, Russo P, Tickoo SK, Akin O, Hakimi AA. Cystic renal cell carcinoma: a report on outcomes of surgery and active surveillance in patients retrospectively identified on pretreatment imaging. J Urol. 2018;200(2):275-82. PMC6050111.

Silagy AW, Kotecha RR, Weng S, Holmes A, Singla N, Mano R, Attalla K, Weiss KL, DiNatale RG, Patil S, Coleman JA, Motzer RJ, Russo P, Voss MH, Hakimi AA. Evolving biological associations of upfront cytoreductive nephrectomy in metastatic renal cell carcinoma.Cancer 2021; Nov 1;127(21):3946-3956. PMC8516697.

Carlo MI, Attalla K, Mazaheri Y, Gupta S, Yildirim O, Murray SJ, Coskey DT, Kotecha R, Lee CH, Feldman DR, Russo P, Patil S, Motzer RJ, Coleman JA, Durack JC, Chen YB, Akin , Hakimi AA*, Voss MH. Phase II Study of Neoadjuvant Nivolumab in Patients with Locally Advanced Clear Cell Renal Cell Carcinoma Undergoing Nephrectomy. Eur Urol. 2022 Jun;81(6):570-573 PMCID: PMC9156541. (*co–senior author).

Reese SW, Khaleel S, Silagy A, Xie A, Eismann L, Vazquez-Rivera K, Oparanozie A, Patil S, Coleman J, Motzer R, Kotecha RR, Russo P, Voss MH, Hakimi AA. Prognostic Factors for Survival in Patients Undergoing Surveillance After Cytoreductive Nephrectomy. J Urol 2023; May. PMID: 37167628