The major focus of Dr. Melissa Fishel’s lab is using clinically relevant systems to study cancer with 3-Dimensional tissue culture and animal models to investigate critical molecular targets that impact upon survival and metastasis. Investigation of pathways involved in redox signaling and DNA repair through APE1/Ref-1 (AP endonuclease1 / Redox effector factor 1) as well as components of the coagulation cascade are being interrogated as therapeutic targets.
Ref-1/APE1
The Fishel lab in collaboration with Mark Kelley’s lab (IU School of Medicine) investigates the use multi-targeted, combination therapy to extend cancer patients’ survival especially in difficult-to-treat, aggressive cancers like pancreatic and pediatric sarcomas (MPNST). Based on its role in response to stress, inflammation, and chemoresistance, we have been developing and characterizing a set of new Ref-1 inhibitors. These studies are built on the structure-affinity relationship (SAR) analysis on parent compound, APX3330 which has completed phase I clinical trials. We seek to understand the mechanisms of Ref-1 signaling and the effects of its inhibition in both tumor cells and the tumor microenvironment in 3D co-culture assays. We also use novel, pathway-driven screening and bioinformatic approaches to discover FDA approved agents to partner with our Ref-1 inhibitors.
FIGURE 1. Example of combination therapy in which the single agents have minimal effects on tumor cell growth (red) but the combination effects are dramatic and yet kill in the presence of the tumor’s protective microenvironment (Cancer-associated fibroblasts, CAFs, green).
Coagulation project
Clinically, pancreatic cancer patients show high expression levels of multiple components of the coagulation system and fibrinolytic system. Dense fibrin networks in the extracellular matrix (ECM) can contribute to drug resistance by acting as a physical barrier, while serving as a molecular bridge between receptors on tumor cells and cells from the microenvironment to promote metastasis. We are investigating the contribution of Fibrin in the tumor and the microenvironment and the effects of targeting fibrinogen on tumor progression. Similarly, to identify mitigation strategies against chemoresistance and drug delivery barriers and immunosuppressive factors, we propose to target other members of the coagulation system, which is highly active in the PDAC TME. In collaboration with Bumsoo Han (Purdue) and Matthew Flick (UNC), we are interrogating strategies to converting the stroma into a chemo- and immune-sensitive TME without making pancreatic cancer cells more aggressive.
FIGURE 2. Immunofluorescence micrographs of normal and cancerous pancreas tissues showing collagen (red), fibrin (green), and nuclei (blue).
Current Research Funding
U01 Pancreatic Ductal Adenocarcinoma (PDAC)
Stromal Reprogramming Consortium (PSRC) (Han/Flick/Fishel, MPI)
Reprogramming to PDAC by Targeting Coagulation in the Tumor Microenvironment
R01 CA167291-08 (Fishel/Kelley, MPI)
Exploiting the Ref-1 node in pancreatic cancer: tailoring new pancreatic cancer therapy using multi-targeted combinations
NIH/NCI R01CA254110 (Fishel/Han MPI)
Investigation of novel signaling protein in 3D and in vivo PDAC models using second generation Ref-1 inhibitors
U01HL143403-01 (Flick/Fishel/Han/Wolberg, MPI)
Consortium Linking Oncology with Thrombosis (CLOT)
Targeting the Plasminogen Activation System to Limit Pancreatic Cancer Progression and Associated Thrombosis
Dept of Defense CDMRP Pancreatic Cancer (Lin PI, Fishel co-I)
Gradient hydrogels for identifying highly invasive pancreatic cancer cells
Recent Publications
Gampala S, Shah F, Lu X, Moon H, Babb O, Ganesh NU, Sandusky G, Hulsey E, Armstrong L, Mosely AL, Han B, Ivan M, Yeh J-R J, Kelley MR, Zhang C^, Fishel ML.^ Ref-1 redox activity alters cancer cell metabolism in pancreatic cancer: Exploiting this novel finding as a potential target. J Exp Clin Cancer Res (2021) 40:251. PMID: 34376225. PMCID: PMC8353735. ^Co-corresponding authors
Mijit M, Wireman R, Armstrong L, Gampala S, Hassan, Z, Schneeweis C, Schneider G, Zhang C, Fishel ML, Kelley MR. RelA is an essential target for enhancing cellular responses to the DNA repair/Ref-1 redox signaling protein and restoring perturbated cellular redox homeostasis in mouse PDAC cells. Frontiers Oncol. 2022 Mar 24; 12:826617.doi10.3389/fonc.2022.826617.eCollection 2022. PMID: 35402225.
Caston RA, Shah F, Starcher CL, Wireman RS, Babb O, Grimard M, McGeown J, Armstrong L, Tong Y, Pili R, Rupert J, Zimmers TA, Elmi AN, Pollok KE, Motea EA, Kelley MR, Fishel ML. Combined inhibition of Ref-1 and STAT3 leads to synergistic tumour inhibition in multiple cancers using 3D and in vivo tumour co-culture models. J Cell Mol Med. 2021 Jan;25(2):784-800. https://doi.org/10.1111/jcmm.16132. PMID: 33274592. PMCID: PMC7812272.
Gampala S, Shah F, Zhang C, Rhodes SD, Babb O, Grimard M, Wireman RS, Rad E, Calver B, Bai R-Y, Staedtke V, Hulsey EL, Saadatzadeh MR, Pollok KE, Tong Y, Smith AE, Clapp DW, Tee AR, Kelley MR, Fishel ML. Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in Malignant Peripheral Nerve Sheath Tumors, British Journal of Cancer 2021. 10.1038/s41416-021-01270-8. PMID: 33658640. PMCID: PMC8076291.
Shouksmith AE, Shah F, Grimard M, Geletu M, Luchman HA, Heaton WL, de Araujo ED, Berger-Becvar A, Gawel JM, Bakhshinyan D,Adile AA, VenugopalC, Johns AE, Al-Qaysi O, Lewis AM, O’Hare T, Deininger MW, Singh SK, Weiss S, Fishel ML*, and Gunning PT*. (2019) Identification and characterization of AES-135, a hydroxamic acid-based HDAC inhibitor that prolongs survival in an orthotopic mouse model of pancreatic cancer. J Med Chem 2019 Feb 18. doi:10.1021/acs.jmedchem.8b01957, PMID: 30776234. * Co-Senior Authorship. (Cover article)
Research Team
Silpa Gampala, PhD
Postdoctoral Fellow
Mahmut Mijiti, PhD
Postdoctoral Fellow
Nayela Chowdhury
Graduate Student
Jacqueline Peil
Research Analyst