Harrison College of Pharmacy

Current Funding

Novel inhibitor for oncogenic RAS for lung cancer
Funder: NIH/NCI 1R01CA254197-01
Date: 2021-2026
Role: Principal Investigator
Description: The long-term goals are to better understand mechanism of action, identify a drug development candidate for IND-enabling safety assessment and establish a mechanistic rationale to select patients for clinical trials based on activated RAS levels.
Scored in 2nd percentile

Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
Funder: NIH/NCI 5 R01 CA197147-04
Date: 2016-2023
Role: Principal Investigator
Description: This project will synthesize and design a novel group of sulindac derivatives relating to a drug development candidate, MCI-048, that contain a methyl-pyrrolidene substitution for lung cancer by targeting phosphodiesterase 10 and to evaluate their efficacy, safety, and mechanism of action using in vitro and in vivo models. Additional aims are to study the involvement of PDE10 in lung tumorigenesis and to study additional analogs.

Novel sulindac derivatives targeting cGMP signaling to enhance cancer immunotherapy
Funder: NIH/NCI 1 R01CA238514-01
Date: 2020-2025
Role: Principal Investigator (MPI with Dr. Gang Zhou, Augusta University)
Description: This proposal will synthesize and characterize a novel series of non-COX inhibitory sulindac derivatives using prototype derivatives that target PDE5 and/or PDE10, while optimizing drug-like properties to increase systemic exposure.

Evaluation of a novel sulindac derivative for breast cancer chemoprevention in a rat model of chemical-induce mammary tumorigenesis
Funder: Breast Cancer Research Foundation Alabama
Date: 2020-2021
Role: Principal Investigator
Description: The purpose of this project is to evaluate a novel ABC transport inhibitor for breast cancer in a mouse model of metastatic disease.

A Novel Non-COX inhibitory Sulindac Derivative for Colorectal Cancer Chemoprevention with Selective PDE10 and Wnt/β-Catenin Inhibitory Activity
Funder: NIH via Fox Chase Cancer Center
Date: 2018-2021
Role: Sub-contract PI
Description: Use a panel of biomarkers to assess chemopreventive activity of a novel PDE10 inhibitor.

A Novel beta-Catenin Blocker That Activates Antitumor Immunity For Breast Cancer
Funder: Breast Cancer Research Foundation Alabama
Date: 2021-2022
Role: Principal Investigator
Description: The purpose of this project is to evaluate a novel PDE10 inhibitor for breast cancer in a mouse model of metastatic disease.

Before the Chicken or the Egg: Modulating Ovarian Hormonal and Inflammatory Inputs to Interrupt Carcinogenesis in a Novel Murine Model of Spontaneous EOC
Funder: Department of Defense Ovarian Cancer Research Program
Date: 2022-2027
Role: Consultant (unpaid)
Description: Evaluate a novel PDE10 inhibitor in a mouse model of ovarian cancer.

Laboratory Personnel

• Dr. Yulia Maxuitenko (pharmacology and toxicology, mouse tumor models)
• Dr. Xi Chen (medicinal and synthetic chemistry, novel anticancer drugs)
• Dr. Adam Keeton (cell biology and biochemistry, signaling transduction)
• Kristy Berry (lab manager and animal technician

External Links

• Pubmed Publications
• Google Scholar
• Curriculum Vitae [PDF]

Research Interests

I have training in pharmacology and cancer research with an interest in cancer drug discovery and development. My research for the past 25 years has studied the molecular basis for the antineoplastic activity of nonsteroidal anti-inflammatory drugs (NSAIDs) (Clin. Cancer Res., 2014). I was the first to report that sulindac and other NSAIDs induce apoptosis by a mechanism unrelated to their cyclooxygenase (COX) inhibitory activity (Cancer Res., 1995). My research in the pharmaceutical industry supported the preclinical development of the non-COX inhibitory sulfone metabolite of sulindac, exisulind, to treat precancerous adenomas in patients with familial adenomatous polyposis (FAP) that was advanced to Phase 3 clinical trials and showed promising efficacy but did not receive FDA approval due to hepatotoxicity.

After returning to academia, I developed a chemical-biology approach involving the synthesis of a large collection of indenes chemically related to sulindac but lacking COX inhibitory activity to develop derivatives with improved efficacy and reduced toxicity. My research showed that sulindac inhibits cancer cell growth by blocking cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) activity, which activates cGMP/PKG signaling to suppress the Wnt/β-catenin mediated transcription (Cancer Res., 2000). This research led to a key discovery that phosphodiesterase 10A is overexpressed in multiple cancers and essential for cancer cell growth and survival (Oncogene, 2014) and the development of a novel sulindac derivative that is highly effective in the Apc Min mouse model of colorectal cancer (Cancer Prevention Res, 2021).

As Endowed Professor and Head of the Drug Discovery and Development Department in the Harrison College of Pharmacy at Auburn University, I lead a multidisciplinary group of scientists with expertise in cancer biology, signal transduction, enzymology, mechanism of action, medicinal chemistry, and in vivo pharmacology.

Recently my research team discovered and characterized a chemically and mechanistically distinct series of RAS inhibitors. A lead compound, ADT-007, emerged that shows ultra-high potency and selectivity to inhibit the growth of cancer cells with constitutively activated RAS. Biochemical, cellular, and biophysical experiments suggests that the growth inhibitory mechanism involves direct binding of ADT-007 to the GTP binding domain of RAS, leading to the blockage of effector (RAF) binding, and suppression of MAPK and PI3K/AKT signaling.

Selected Publications

131 publications, 9197 citations; H-index of 51

RAS-related publications

• Albert Kryan Kwan; Gary A. Piazza; Adam B. Keeton; Caio Abner Leite (2021). “The Path to the Clinic:  A Comprehensive Review on Direct KRASG12C Inhibitors”, J. Exp. And Clin. Cancer Res.  doi:10.1186/s13046-021-02225-w
• Coley A.B., Ward A., Keeton A.B., Chen X., Maxuitenko Y., Prakash A., Li F., Foote J.B., Buchsbaum D.J., and Piazza G.A. (2021).  “Pan-RAS inhibitors: Hitting multiple RAS isozymes with one stone”.  Advances in Cancer Research, Academic Press.  ISSN 0065-230X.
• Ward A.B, Keeton A.B., Chen X., Mattox T.E., Coley A.B., Maxuitenko Y.Y., Buchsbaum D.J., Randall T.D., Zhou G., and Piazza G.A. (2020) “Enhancing anticancer activity of checkpoint immunotherapy by targeting RAS”. MedComm. 1, 121-128.
• Mattox T.E., Chen X., Maxuitenko, Y.Y., Keeton, A.B. and Piazza G.A. (2020) “Exploiting RAS nucleotide cycling as a strategy for drugging RAS-driven cancer”. In Progress and Challenges with Inhibition of K-Ras GTPase in Cancer, International Journal Molecular Sciences, 21(1): 141. PMID: 31878223; PMCID: PMC6982188.
• Keeton, A.B., Salter, E.A., and Piazza G.A. (2017) “Ras drug-effector interactions as a novel drug target”. Cancer Research, 77: 1–6. PMID: 28062402; PMCID: PMC5243175.

PDE10-related publications

• Lee, K., J., Chang, W., Ramirez-Alcantara, V.,  Chen, X., Valiyaveettil, J., Gavin, E., Musiyenko, A., Madeira da Silva, L., Annamdevula, N.S., Leavesley, S.J.,  Ward, A., Mattox, T., Wierzbicki, A., Salter, A., Lindsey, A. S., Andrews, J., Zhu, B., Wood, C., Neese, A., Nguyen, A., Berry, K., Maxuitenko, Y.,  Moyer, M. P., Gorman, G., Coward, L., Keeton, A.B., Cooper, H., Clapper, M., and G. A. Piazza (2021) “PDE10 inhibition selectively blocks Wnt/β-catenin signaling to suppress colon tumorigenesis”.  Accepted for publication 9/21/2021, Cancer Prevention Research (Featured on cover).
• Zhu, B., Lindsey, A., Li, N., Lee, K., Ramirez-Alcantara, V., Canzoneri, J.C., Fajardo, A., Madeira da Silva, L., Thomas, M., Piazza, J.T., Yet, L., Eberhardt, B.T., Gurpinar, E., Otali, D., Grizzle, W., Valiyaveettil, J., Chen, X, Keeton AB, and Piazza G.A. (2017) “Phosphodiesterase 10A is overexpressed in lung tumor cells and inhibitors selectively suppress growth by blocking β-catenin and MAPK signaling”. Oncotarget, 8:69264-69280. PMID: 29050202; PMCID: PMC5642477
• Lee, K., Lindsey, A., Li, N., Gary, B., Andrews, J., Keeton, A. and G. Piazza (2016) “β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG".  Oncotarget. 7: 5353-65. PMCID: PMC4868691.
• Li, N., Lee, K., Xi, Y., Zhu, B., Gary, B.D., Ramírez-Alcántara, V., Gurpinar, E., Canzoneri, J.C., Fajardo, A., Sigler, S., Piazza, J.T., Chen, X., Andrews, J., Thomas, M., Lu, W., Li, Y., Laan, D.J., Moyer, M.P., Russo, S., Eberhardt, B.T., Yet, L., Keeton, A.B., Grizzle, W.E., and G.A. Piazza (2014). “Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and β-catenin-dependent TCF transcriptional activity” (2015) Oncogene 34: 1499-1509. PMID:24704829; PMCID: PMC4212019.

Preclinical drug development

• Piazza, G.A., Thompson, W. J., Pamukcu, R., Whitehead, C., Li, H., Fetter, J., Gresh, B., Klein-Szanto, A., Farnell, D., Eto, I., and C. J., Grubbs (2001) “Exisulind, a novel proapoptotic drug, inhibits rat urinary bladder tumorigenesis”. Cancer Research 61: 3961-3968.
• Malkinson, A.M., Koshi, K.M., Dwyer-Nield, L.D., Rice, P.L., Rioux, N., Castonguay, A., Ahnen, D.J., Thompson, H., Pamukcu, R. and Piazza G.A. (1998) “Inhibition of NNK-induced mouse lung tumor formation by FGN-1 (sulindac sulfone)”. Carcinogenesis 19:1353 - 1356.
• Thompson, H.J., Jiang, C., Lu, X., Mehta, R.G., Piazza, G.A., Paranka, N.S., Pamukcu, R. and D.J. Ahnen (1997) “Sulfone metabolite of sulindac inhibits mammary carcinogenesis”. Cancer Research 57: 267 - 272.
• Piazza, G.A., Alberts, D.S., Hixson, L.J., Paranka, N.S., Bogert, C., Guillen, J.M., Brendel, K., Gross, P., Sperl, G., Ritchie, J., Burt, R. W., Ellsworth, L., Ahnen, D.J. and R. Pamukcu (1997). “Sulindac sulfone inhibits azoxymethane-induced colon carcinogenesis without reducing prostaglandin levels”. Cancer Research 57: 2909 - 2916.

Drug Discovery

• Emmanouilidi A., Ruban E., Casari I., Akkaya B.G., Maffucci T., Furic L., Guffanti F., Broggini M., Chen X., Maxuitenko Y., Keeton A, Piazza G.A., Linton K.J. and Falasca M. (2020) “Inhibition of the lysophosphatidylinositol transporter ABCC1 reduces prostate cancer cell growth and sensitizes to chemotherapy” Cancers 12: 2022-41.
• Ding Z., Shi H., Fesenkova K., Aboelella N., Park E., Liu Z., Pei L., Li J., McIndoe R., Piazza G.A., Blazar B., Munn D., and Zhou G. (2020) “Persistent STAT5 activation in CD4+ T cells induces transcriptional and epigenetic remodeling to drive polyfunctionality and antitumor immunity”, Science Immunology, 5, DOI: 10.1126/sciimmunol. aba5962
• Piazza G.A., Ward A., Chen X., Maxuitenko Y., Coley A., Aboelella N.S., Buchsbaum D.J., Boyd M.R., Keeton A.B., and Zhou G. (2020) “PDE5 and PDE10 inhibition activate cGMP/PKG signaling to block Wnt/β-catenin transcription, cancer cell growth, and tumor immunity” Drug Discovery Today 25: 1521-27.
• Adamska, A., Domenichini, A., Capone, E., Damiani, V., Akkaya, BG, Linton, KJ, Di Sebastiano, P., Chen, X., Keeton, AB, Ramirez-Alcantara, V., Maxuitenko, Y., Piazza, GA, De Laurenzi, V., Sala, G., and M. Falasca (2019) “Pharmacological inhibition of ABCC3 slows tumour progression in animal models of pancreatic cancer” Journal of Experimental & Clinical Cancer Research 38: 7-14.
• Abdel-Halim M., Sigler S., Racheed N.A., Hammam M.A., Hefnawy A.M., Fathalla R.K., Maher A., Maxuitenko Y., Keeton A.B., Hartmann R.W., Engel M., Piazza, G.A. and Abadi A.H. (2021) “From celecoxib to a novel class of phosphodiesterase 5 Inhibitors: Trisubstituted pyrazolines as novel phosphodiesterase 5 inhibitors with extremely high potency and PDE isozyme selectivity”. J. Med Chem. 64, 8, 4462–4477.
• Hafez D.E., Hafez E., Eddiasty I., Shih S., Chen L., Hong Y., Lin H., Keeton A.B., Piazza G.A., Abdel-Halim M., and Abadi A.H. (2021). “Novel thiazolidine derivatives as potent selective pro-apoptotic agents”, Bioorganic Chem. 105143.
• Li, H., Keeton, A. Maddox, C., Rasmussen, L., Hobrath, J., White, L., Piazza, G.A., Kim, J. and T. Waldman (2011) “A high throughput screen with isogenic PTEN+/+ and PTEN-/- cells identifies CID1340132, a novel compound with selective cytotoxicity towards PTEN and PIK3CA mutant human colon cancer cells”. Journal of Biomolecular Screening 16: 383-393. PMID:21335596; PMCID: PMC4381441.
• Zhang, L., Nebane, M., Wennerberg, K., Li, Y., Neubauer, V., McKellip, S., Rasmussen, L., Shindo, N., Sosa, M., Maddry, J. Ananthan, S., Piazza, G.A., White, E.L., and E. Harsay (2010) “A high-throughput screen for chemical inhibitors of exocytic transport in yeast”. Chem Bio Chem 11: 1291-1301.