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Inna  Smalley

Inna Smalley, PhD

Program: Metabolism and Physiology

Research Program: Cancer Biology & Evolution Program

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  • Overview

    The I. Smalley Lab investigates how intra-tumoral heterogeneity facilitates drug resistance and dissemination, with a focus on single cell analysis and metabolism


    • Cutaneous Oncology
    • Metabolism and Physiology
    • Cancer Biology & Evolution Program

    Education & Training


    • University of South Florida, PhD - Cancer Biology
  • Research Interest

    Dr. Smalley has largely focused on developing novel therapeutic rationales for treating BRAF- and NRAS-mutant melanoma, with an emphasis on the role of the tumor microenvironment in drug resistance. This includes recent findings on the mechanisms of drug resistance in BRAF-mutant melanoma that rely on extracellular matrix remodeling and fibroblast activation. The current studies are focused on exploring how intra-tumoral heterogeneity facilitates tumor growth, drug resistance and dissemination, with a special focus on single cell analysis and metabolism-associated signaling. She would like to elucidate what drives tumor cells to certain metastatic sites, including the brain and leptomeninges, as well as the mechanism supporting their survival in different microenvironments. Dr. Smalley believes that the future treatment of melanoma lies in personalized, rational drug combinations that will turn a terminal disease into a manageable chronic illness. My career goal is to develop efficacious treatment strategies for patients with CNS metastasis and late-stage disease.

  • Publications

    • Law V, Smalley I, Evernden BR, Baldwin M, Smalley KSM, Forsyth PA. Ex Vivo Culture of Circulating Tumor Cells in the Cerebral Spinal Fluid from Melanoma Patients to Study Melanoma-Associated Leptomeningeal Disease. J Vis Exp. 2024 Mar.(205). Pubmedid: 38619274.
    • Wallace G, Kundalia R, Vallebuona E, Cao B, Kim Y, Forsyth P, Soyano A, Smalley I, Pina Y. Factors associated with overall survival in breast cancer patients with leptomeningeal disease (LMD): a single institutional retrospective review. Breast Cancer Res. 2024 Mar.26(1):55. Pubmedid: 38553702. Pmcid: PMC10979566.
    • Alhaddad H, Ospina OE, Khaled ML, Ren Y, Vallebuona E, Boozo MB, Forsyth PA, Pina Y, Macaulay R, Law V, Tsai KY, Cress WD, Fridley B, Smalley I. Spatial transcriptomics analysis identifies a tumor-promoting function of the meningeal stroma in melanoma leptomeningeal disease. Cell Rep Med. 2024 Jun.5(6):101606. Pubmedid: 38866016. Pmcid: PMC11228800.
    • Wilcox JA, Chukwueke UN, Ahn MJ, Aizer AA, Bale TA, Brandsma D, Brastianos PK, Chang S, Daras M, Forsyth P, Garzia L, Glantz M, Oliva ICG, Kumthekar P, Le Rhun E, Nagpal S, O'Brien B, Pentsova E, Lee EQ, Remsik J, Rudà R, Smalley I, Taylor MD, Weller M, Wefel J, Yang JT, Young RJ, Wen PY, Boire AA. Leptomeningeal metastases from solid tumors: A SNO and ASCO consensus review on clinical management and future directions. Neurooncol. 2024 Jun. Pubmedid: 38902944.
    • Smalley I, Boire A, Brastianos P, Kluger HM, Hernando-Monge E, Forsyth PA, Ahmed KA, Smalley KSM, Ferguson S, Davies MA, Glitza Oliva IC. Leptomeningeal disease in melanoma: An update on the developments in pathophysiology and clinical care. Pigment Cell Melanoma Res. 2024 Jan.37(1):51-67. Pubmedid: 37622466.
    • Eroglu Z, Chen YA, Smalley I, Li J, Markowitz JK, Brohl AS, Tetteh L, Taylor H, Sondak VK, Khushalani NI, Smalley KSM. Combined BRAF, MEK, and heat-shock protein 90 inhibition in advanced BRAF V600-mutant melanoma. Cancer. 2024 Jan.130(2):232-243. Pubmedid: 37776537.
    • Khaled ML, Tarhini AA, Forsyth PA, Smalley I, Piña Y. Leptomeningeal Disease (LMD) in Patients with Melanoma Metastases. Cancers (Basel). 2023 Mar.15(6). Pubmedid: 36980770. Pmcid: PMC10047692.
    • Khaled ML, Ren Y, Kundalia R, Alhaddad H, Chen Z, Wallace GC, Evernden B, Ospina OE, Hall M, Liu M, Darville LNF, Izumi V, Chen YA, Pilon-Thomas S, Stewart PA, Koomen JM, Corallo SA, Jain MD, Robinson TJ, Locke FL, Forsyth PA, Smalley I. Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease. bioRxiv. 2023 Dec. Pubmedid: 38187773. Pmcid: PMC10769272.
    • Alhaddad H, Ospina OE, Khaled ML, Ren Y, Forsyth P, Pina Y, Macaulay R, Law V, Tsai KY, Cress WD, Fridley B, Smalley I. Spatial transcriptomics analysis identifies a unique tumor-promoting function of the meningeal stroma in melanoma leptomeningeal disease. bioRxiv. 2023 Dec. Pubmedid: 38187574. Pmcid: PMC10769278.
    • Smalley I, Smalley KSM. Space Is the Place: Mapping the Cell-Cell Interactions That Predict Immunotherapy Responses in Melanoma. Cancer Res. 2022 Sep.82(18):3198-3200. Pubmedid: 36111402.
    • Law V, Chen Z, Vena F, Smalley I, Macaulay R, Evernden BR, Tran N, Pina Y, Puskas J, Caceres G, Bayle S, Johnson J, Liu JKC, Etame A, Vogelbaum M, Rodriguez P, Duckett D, Czerniecki B, Chen A, Smalley KSM, Forsyth PA. A preclinical model of patient-derived cerebrospinal fluid circulating tumor cells for experimental therapeutics in leptomeningeal disease from melanoma. Neurooncol. 2022 Oct.24(10):1673-1686. Pubmedid: 35213727. Pmcid: PMC9527526.
    • Li J, Smalley I, Chen Z, Wu JY, Phadke MS, Teer JK, Nguyen T, Karreth FA, Koomen JM, Sarnaik AA, Zager JS, Khushalani NI, Tarhini AA, Sondak VK, Rodriguez PC, Messina JL, Chen YA, Smalley KSM. Single-cell Characterization of the Cellular Landscape of Acral Melanoma Identifies Novel Targets for Immunotherapy. Clin Cancer Res. 2022 May.28(10):2131-2146. Pubmedid: 35247927. Pmcid: PMC9106889.
    • Sriramareddy SN, Faião-Flores F, Emmons MF, Saha B, Chellappan S, Wyatt C, Smalley I, Licht JD, Durante MA, Harbour JW, Smalley KSM. HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma. Cancer Gene Ther. 2022 Dec.29(12):1840-1846. Pubmedid: 35332245. Pmcid: PMC9508287.
    • Ospina OE, Wilson CM, Soupir AC, Berglund A, Smalley I, Tsai KY, Fridley B. spatialGE: quantification and visualization of the tumor microenvironment heterogeneity using spatial transcriptomics. Bioinformatics. 2022 Apr.38(9):2645-2647. Pubmedid: 35258565.
    • Phadke MS, Chen Z, Li J, Mohamed E, Davies MA, Smalley I, Duckett D, Palve V, Czerniecki BJ, Forsyth PA, Noyes D, Adeegbe DO, Eroglu Z, Nguyen KT, Tsai KY, Rix U, Burd CE, Chen YA, Rodriguez PC, Smalley KSM. Targeted Therapy Given after Anti-PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity. Cancer Immunol Res. 2021 May.9(5):554-567. Pubmedid: 33653716. Pmcid: PMC8102376.
    • Smalley I, Chen Z, Phadke MS, Li J, Yu X, Wyatt C, Evernden B, Messina JL, Sarnaik A, Sondak VK, Zhang C, Law V, Tran N, Etame A, Macaulay RJB, Eroglu Z, Forsyth PA, Rodriguez PC, Chen YA, Smalley KSM. Single-Cell Characterization of the Immune Microenvironment of Melanoma Brain and Leptomeningeal Metastases. Clin Cancer Res. 2021 Jul.27(14):4109-4125. Pubmedid: 34035069. Pmcid: PMC8282775.
    • Law V, Baldwin M, Ramamoorthi G, Kodumudi K, Tran N, Smalley I, Duckett D, Kalinski P, Czerniecki B, Smalley KSM, Forsyth PA. A Murine Ommaya Xenograft Model to Study Direct-Targeted Therapy of Leptomeningeal Disease. J Vis Exp. 2021 Jan.(167). Pubmedid: 33586709. Pmcid: PMC9014476.
    • Zhang C, Smalley I, Emmons MF, Sharma R, Izumi V, Messina J, Koomen JM, Pasquale EB, Forsyth PA, Smalley KSM. Noncanonical EphA2 Signaling Is a Driver of Tumor-Endothelial Cell Interactions and Metastatic Dissemination in BRAF Inhibitor‒Resistant Melanoma. J Invest Dermatol. 2021 Apr.141(4):840-851.e4. Pubmedid: 32890629. Pmcid: PMC7921215.
    • Smalley I, Law V, Wyatt C, Evernden B, Fang B, Koomen JM, Welsh EA, Macaulay RJB, Forsyth PA, Smalley KSM. Proteomic Analysis of CSF from Patients with Leptomeningeal Melanoma Metastases Identifies Signatures Associated with Disease Progression and Therapeutic Resistance. Clin Cancer Res. 2020 May.26(9):2163-2175. Pubmedid: 31924735. Pmcid: PMC7196498.
    • Glitza IC, Smalley KSM, Brastianos PK, Davies MA, McCutcheon I, Liu JKC, Ahmed KA, Arrington JA, Evernden BR, Smalley I, Eroglu Z, Khushalani N, Margolin K, Kluger H, Atkins MB, Tawbi H, Boire A, Forsyth P. Leptomeningeal disease in melanoma patients: An update to treatment, challenges, and future directions. Pigment Cell Melanoma Res. 2020 Jul.33(4):527-541. Pubmedid: 31916400.
    • Smalley I, Kim E, Li J, Spence P, Wyatt CJ, Eroglu Z, Sondak VK, Messina JL, Babacan NA, Maria-Engler SS, De Armas L, Williams SL, Gatenby RA, Chen YA, Anderson ARA, Smalley KSM. Leveraging transcriptional dynamics to improve BRAF inhibitor responses in melanoma. EBioMedicine. 2019 Oct.48:178-190. Pubmedid: 31594749. Pmcid: PMC6838387.
    • Eroglu Z, Holmen SL, Chen Q, Khushalani NI, Amaravadi R, Thomas R, Ahmed KA, Tawbi H, Chandra S, Markowitz J, Smalley I, Liu JKC, Ann Chen Y, Najjar YG, Karreth FA, Abate-Daga D, Glitza IC, Sosman JA, Sondak VK, Bosenberg M, Herlyn M, Atkins MB, Kluger H, Margolin K, Forsyth PA, Davies MA, Smalley KSM. Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities. Pigment Cell Melanoma Res. 2019 May.32(3):458-469. Pubmedid: 30712316. Pmcid: PMC7771318.
    • Eroglu Z, Chen YA, Gibney GT, Weber JS, Kudchadkar RR, Khushalani NI, Markowitz J, Brohl AS, Tetteh LF, Ramadan H, Arnone G, Li J, Zhao X, Sharma R, Darville LNF, Fang B, Smalley I, Messina JL, Koomen JM, Sondak VK, Smalley KSM. Combined BRAF and HSP90 Inhibition in Patients with Unresectable BRAF V600E-Mutant Melanoma. Clin Cancer Res. 2018 Nov.24(22):5516-5524. Pubmedid: 29674508. Pmcid: PMC6195480.
    • Abate-Daga D, Ramello MC, Smalley I, Forsyth PA, Smalley KSM. The biology and therapeutic management of melanoma brain metastases. Biochem Pharmacol. 2018 Jul.153:35-45. Pubmedid: 29278675. Pmcid: PMC5959746.
    • Phadke M, Rix LLR, Smalley I, Bryant AT, Luo Y, Lawrence HR, Schaible BJ, Chen YA, Rix U, Smalley KSM. Dabrafenib inhibits the growth of BRAF-WT cancers through CDK16 and NEK9 inhibition. Mol Oncol. 2018 Jan.12(1):74-88. Pubmedid: 29112787. Pmcid: PMC5748485.
    • Smalley I, Smalley KSM. ERK Inhibition: A New Front in the War against MAPK Pathway-Driven Cancers?. Cancer Discov. 2018 Feb.8(2):140-142. Pubmedid: 29431672.
    • Li J, Smalley I, Schell MJ, Smalley KSM, Chen YA. SinCHet: a MATLAB toolbox for single cell heterogeneity analysis in cancer. Bioinformatics. 2017 Sep.33(18):2951-2953. Pubmedid: 28472395. Pmcid: PMC5870537.
    • Robinson JP, Rebecca VW, Kircher DA, Silvis MR, Smalley I, Gibney GT, Lastwika KJ, Chen G, Davies MA, Grossman D, Smalley KSM, Holmen SL, VanBrocklin MW. Resistance mechanisms to genetic suppression of mutant NRAS in melanoma. Melanoma Res. 2017 Dec.27(6):545-557. Pubmedid: 29076949. Pmcid: PMC5683096.
    • Smalley KS, Fedorenko IV, Kenchappa R, Sahebjam S, Forsyth PA. Managing leptomeningeal melanoma metastases in the era of immune and targeted therapy. Int J Cancer. 2016 Sep.139(6):1195-1201. Pubmedid: 27084046. Pmcid: PMC4939138.
    • Fedorenko IV, Evernden B, Kenchappa RS, Sahebjam S, Ryzhova E, Puskas J, McIntosh L, Caceres G, Magliocco A, Etame A, Harbour JW, Smalley KS, Forsyth PA. A rare case of leptomeningeal carcinomatosis in a patient with uveal melanoma: case report and review of literature. Melanoma Res. 2016 Oct.26(5):481-486. Pubmedid: 27285292. Pmcid: PMC5502096.
    • Fedorenko IV, Abel EV, Koomen JM, Fang B, Wood ER, Chen YA, Fisher KJ, Iyengar S, Dahlman KB, Wargo JA, Flaherty KT, Sosman JA, Sondak VK, Messina JL, Gibney GT, Smalley KS. Fibronectin induction abrogates the BRAF inhibitor response of BRAF V600E/PTEN-null melanoma cells. Oncogene. 2016 Mar.35(10):1225-1235. Pubmedid: 26073081. Pmcid: PMC4679729.
    • Sharma R, Fedorenko I, Spence PT, Sondak VK, Smalley KS, Koomen JM. Activity-Based Protein Profiling Shows Heterogeneous Signaling Adaptations to BRAF Inhibition. J Proteome Res. 2016 Dec.15(12):4476-4489. Pubmedid: 27934295. Pmcid: PMC5642956.
    • Fedorenko IV, Smalley KS. The complexity of microenvironment-mediated drug resistance. Genes Cancer. 2015 Sep.6(9-10):367-368. Pubmedid: 26622938. Pmcid: PMC4633163.
    • Phadke M, Gibney GT, Rich CJ, Fedorenko IV, Chen Ann Y, Kudchadkar RR, Sondak VK, Weber J, Messina JL, Smalley KS. XL888 Limits Vemurafenib-Induced Proliferative Skin Events by Suppressing Paradoxical MAPK Activation. J Invest Dermatol. 2015 Oct.135(10):2542-2544. Pubmedid: 26039542. Pmcid: PMC4567904.
    • Paraiso KH, Thakur MD, Fang B, Koomen JM, Fedorenko IV, John JK, Tsao H, Flaherty KT, Sondak VK, Messina JL, Pasquale EB, Villagra A, Rao UN, Kirkwood JM, Meier F, Sloot S, Gibney GT, Stuart D, Tawbi H, Smalley KS. Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype. Cancer Discov. 2015 Mar.5(3):264-273. Pubmedid: 25542447. Pmcid: PMC4355213.
    • Smalley KS, Fedorenko IV. Inhibition of BRAF and BRAF+MEK drives a metastatic switch in melanoma. Mol Cell Oncol. 2015 Mar.2(4):e1008291. Pubmedid: 27308505. Pmcid: PMC4905349.
    • Fedorenko IV, Gibney GT, Sondak VK, Smalley KS. Beyond BRAF: where next for melanoma therapy?. Brit J Cancer. 2015 Jan.112(2):217-226. Pubmedid: 25180764. Pmcid: PMC4453440.
    • Fedorenko IV, Fang B, Munko AC, Gibney GT, Koomen JM, Smalley KS. Phosphoproteomic analysis of basal and therapy-induced adaptive signaling networks in BRAF and NRAS mutant melanoma. Proteomics. 2015 Jan.15(2-3):327-339. Pubmedid: 25339196. Pmcid: PMC4389901.
    • Fedorenko IV, Wargo JA, Flaherty KT, Messina JL, Smalley KS. BRAF Inhibition Generates a Host-Tumor Niche that Mediates Therapeutic Escape. J Invest Dermatol. 2015 Dec.135(12):3115-3124. Pubmedid: 26302068. Pmcid: PMC4648653.
    • Fedorenko IV, Fang B, Koomen JM, Gibney GT, Smalley KS. Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not BRAF-mutant melanoma. Melanoma Res. 2014 Oct.24(5):448-453. Pubmedid: 24950457. Pmcid: PMC4384823.
    • Rebecca VW, Massaro RR, Fedorenko IV, Sondak VK, Anderson AR, Kim E, Amavaradi RK, Maria-Engler SS, Messina JL, Gibney GT, Kudchadkar RR, Smalley KS. Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma. Pigment Cell Melanoma Res. 2014 May.27(3):465-478. Pubmedid: 24490764. Pmcid: PMC3988257.
    • Rebecca VW, Wood ER, Fedorenko IV, Paraiso KH, Haarberg HE, Chen Y, Xiang Y, Sarnaik A, Gibney GT, Sondak VK, Koomen JM, Smalley KS. Evaluating melanoma drug response and therapeutic escape with quantitative proteomics. Mol Cell Proteomics. 2014 Jul.13(7):1844-1854. Pubmedid: 24760959. Pmcid: PMC4083119.
    • Sloot S, Fedorenko IV, Smalley KS, Gibney GT. Long-term effects of BRAF inhibitors in melanoma treatment: friend or foe?. Expert Opin Pharmacother. 2014 Apr.15(5):589-592. Pubmedid: 24456413.
    • Fedorenko IV, Gibney GT, Smalley KS. NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene. 2013 Jun.32(25):3009-3018. Pubmedid: 23069660. Pmcid: PMC3978385.
    • Gibney GT, Messina JL, Fedorenko IV, Sondak VK, Smalley KS. Paradoxical oncogenesis--the long-term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol. 2013 Jul.10(7):390-399. Pubmedid: 23712190. Pmcid: PMC3983565.
    • Kim E, Rebecca VW, Fedorenko IV, Messina JL, Mathew R, Maria-Engler SS, Basanta D, Smalley KS, Anderson AR. Senescent fibroblasts in melanoma initiation and progression: an integrated theoretical, experimental, and clinical approach. Cancer Res. 2013 Dec.73(23):6874-6885. Pubmedid: 24080279. Pmcid: PMC3926439.
    • Pimiento JM, Larkin EM, Smalley KS, Wiersma GL, Monks NR, Fedorenko IV, Peterson CA, Nickoloff BJ. Melanoma genotypes and phenotypes get personal. Lab Invest. 2013 Aug.93(8):858-867. Pubmedid: 23817084.
    • Fedorenko IV, Paraiso KH, Smalley KS. Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma. Biochem Pharmacol. 2011 Aug.82(3):201-209. Pubmedid: 21635872. Pmcid: PMC4001781.
    • Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen YA, Munko AC, Wood E, Fedorenko IV, Sondak VK, Anderson AR, Ribas A, Palma MD, Nathanson KL, Koomen JM, Messina JL, Smalley KS. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011 Apr.71(7):2750-2760. Pubmedid: 21317224. Pmcid: PMC3070772.
    • Song D, Fedorenko I, Pensky M, Qian W, Tockman MS, Zhukov TA. Quantificational and statistical analysis of the differences in centrosomal features of untreated lung cancer cells and normal cells. Anal Quant Cytol Histol. 2010 Oct.32(5):280-290. Pubmedid: 22043504.
    • Paraiso KH, Fedorenko IV, Cantini LP, Munko AC, Hall M, Sondak VK, Messina JL, Flaherty KT, Smalley KS. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Brit J Cancer. 2010 Jun.102(12):1724-1730. Pubmedid: 20531415. Pmcid: PMC2883709.
  • Grants

    • Title: How the aging tumor microenvironment affects the outgrowth of leptomeningeal metastases
      Sponsor: Amer Cancer Society
      PI (Contact): Smalley, I.
    • Title: Improving therapy for leptomeningeal Non-Hodgkin B cell lymphoma by targeting the metabolic tumor microenvironment
      Sponsor: Amer Cancer Society
      PI: Smalley, I.
    • Title: Defining and targeting the immune-suppressive metabolic microenvironment of leptomeningeal melanoma metastases
      Sponsor: Nat Institutes of Health
      PI: Smalley, I.
    • Title: Defining the Role of Metabolic Heterogeneity in Melanoma Dissemination and Therapy Escape
      Sponsor: Nat Institutes of Health
      PI: Smalley, I.
    • Title: Tumor-stroma metabolic crosstalk in melanoma brain metastases
      Sponsor: Melanoma Research Alliance (MRA)
      PI: Smalley, I.

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