Mark R. Kelley

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https://hdl.handle.net/1805/6602

Dr. Kelley is the 2017 recipient of the Bantz Petronio Translating Research Into Practice Award

Since joining the Department of Pediatrics at the IU School of Medicine in 1993, Dr, Kelley’s work has focused on translational research in DNA damage and repair, specifically, to determine how those activities can be exploited therapeutically to treat cancers and protect normal cells from DNA damage.

He has focused specifically on the enzyme called APE1 as a therapeutic target in cancers and other diseases. Dr. Kelley discovered and has been developing a specific inhibitor of APE1 which he is now translating to clinical trials. This work has also led to the creation of a biotechnology company called Apexian Pharmaceuticals, of which Dr. Kelley is the Chief Scientific Founder and Officer.

The first drug developed has recently been approved by the FDA for Phase 1 clinical trials in cancer patients scheduled to begin in 2017. The drug has potential uses in a number of cancers including ovarian, colon, bladder, pancreatic, leukemia, and other adult and pediatric cancers.

He is also exploring the use of the target APE1 and the drug to prevent a major side-effect of cancer treatments called chemotherapy-induced peripheral neuropathy (CIPN).

Dr. Kelley is committed to fast-tracking collaboration and translational research efforts in order to find more effective cancer treatments. He also mentors and encourages students, post-doctorates, fellows and junior faculty in translating their research into practice to expand the number of discoveries that help solve problems and make life better.

Professor Kelley's application of a business model to support research planning and implementation is another example of how IUPUI's faculty members are TRANSLATING their RESEARCH INTO PRACTICE.

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Now showing 1 - 10 of 74

Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic
(Springer NPG, 2017-06-08) Shah, Fenil; Logsdon, Derek; Messmann, Richard A.; Fehrenbacher, Jill C.; Fishel, Melissa L.; Kelley, Mark R.; Department of Pediatrics, School of Medicine
Reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease (Ref-1/APE1) is a critical node in tumor cells, both as a redox regulator of transcription factor activation and as part of the DNA damage response. As a redox signaling protein, Ref-1/APE1 enhances the transcriptional activity of STAT3, HIF-1α, nuclear factor kappa B, and other transcription factors to promote growth, migration, and survival in tumor cells as well as inflammation and angiogenesis in the tumor microenvironment. Ref-1/APE1 is activated in a variety of cancers, including prostate, colon, pancreatic, ovarian, lung and leukemias, leading to increased aggressiveness. Transcription factors downstream of Ref-1/APE1 are key contributors to many cancers, and Ref-1/APE1 redox signaling inhibition slows growth and progression in a number of tumor types. Ref-1/APE1 inhibition is also highly effective when paired with other drugs, including standard-of-care therapies and therapies targeting pathways affected by Ref-1/APE1 redox signaling. Additionally, Ref-1/APE1 plays a role in a variety of other indications, such as retinopathy, inflammation, and neuropathy. In this review, we discuss the functional consequences of activation of the Ref-1/APE1 node in cancer and other diseases, as well as potential therapies targeting Ref-1/APE1 and related pathways in relevant diseases. APX3330, a novel oral anticancer agent and the first drug to target Ref-1/APE1 for cancer is entering clinical trials and will be explored in various cancers and other diseases bringing bench discoveries to the clinic.
Role of the DNA Base Excision Repair Protein, APE1 in Cisplatin, Oxaliplatin, or Carboplatin Induced Sensory Neuropathy
(PLOS, 2014-09-04) Kelley, Mark R.; Jiang, Yanlin; Guo, Chunlu; Reed, April; Meng, Hongdi; Vasko, Michael R.; Department of Pediatrics, School of Medicine
Although chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of platinum drugs, the mechanisms of this toxicity remain unknown. Previous work in our laboratory suggests that cisplatin-induced CIPN is secondary to DNA damage which is susceptible to base excision repair (BER). To further examine this hypothesis, we studied the effects of cisplatin, oxaliplatin, and carboplatin on cell survival, DNA damage, ROS production, and functional endpoints in rat sensory neurons in culture in the absence or presence of reduced expression of the BER protein AP endonuclease/redox factor-1 (APE1). Using an in situ model of peptidergic sensory neuron function, we examined the effects of the platinum drugs on hind limb capsaicin-evoked vasodilatation. Exposing sensory neurons in culture to the three platinum drugs caused a concentration-dependent increase in apoptosis and cell death, although the concentrations of carboplatin were 10 fold higher than cisplatin. As previously observed with cisplatin, oxaliplatin and carboplatin also increased DNA damage as indicated by an increase in phospho-H2AX and reduced the capsaicin-evoked release of CGRP from neuronal cultures. Both cisplatin and oxaliplatin increased the production of ROS as well as 8-oxoguanine DNA adduct levels, whereas carboplatin did not. Reducing levels of APE1 in neuronal cultures augmented the cisplatin and oxaliplatin induced toxicity, but did not alter the effects of carboplatin. Using an in vivo model, systemic injection of cisplatin (3 mg/kg), oxaliplatin (3 mg/kg), or carboplatin (30 mg/kg) once a week for three weeks caused a decrease in capsaicin-evoked vasodilatation, which was delayed in onset. The effects of cisplatin on capsaicin-evoked vasodilatation were attenuated by chronic administration of E3330, a redox inhibitor of APE1 that serendipitously enhances APE1 DNA repair activity in sensory neurons. These outcomes support the importance of the BER pathway, and particularly APE1, in sensory neuropathy caused by cisplatin and oxaliplatin, but not carboplatin and suggest that augmenting DNA repair could be a therapeutic target for CIPN.
Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models
(AACR, 2016-11-01) Logsdon, Derek P.; Grimard, Michelle; Luo, Meihua; Shahda, Safi; Jiang, Yanlin; Tong, Yan; Yu, Zhangsheng; Zyromski, Nicholas; Schipani, Ernestina; Carta, Fabrizio; Supuran, Claudiu T.; Korc, Murray; Ivan, Mircea; Kelley, Mark R.; Fishel, Melissa L.; Department of Pediatrics, School of Medicine
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multifunctional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia-inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as a part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with the hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo three-dimensional tumor coculture model demonstrates dramatic enhancement of APE1/Ref-1–induced cell killing upon dual targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development; therefore, these studies have the potential to direct novel PDAC therapeutic treatment.
Longitudinal Bioluminescence Imaging of Primary Versus Abdominal Metastatic Tumor Growth in Orthotopic Pancreatic Tumor Models in NSG Mice
(LWW, 2015-01) Shannon, Harlan E.; Fishel, Melissa L.; Xie, Jingwu; Gu, Dongsheng; McCarthy, Brian P.; Riley, Amanda A.; Sinn, Anthony L.; Silver, Jayne M.; Peterman, Kacie; Kelley, Mark R.; Hanenberg, Helmut; Korc, Murray; Pollok, Karen E.; Territo, Paul R.; Department of Pediatrics, School of Medicine
Objectives: The purpose of the present study was to develop and validate noninvasive bioluminescence imaging methods for differentially monitoring primary and abdominal metastatic tumor growth in mouse orthotopic models of pancreatic cancer. Methods: A semiautomated maximum entropy segmentation method was implemented for the primary tumor region of interest, and a rule-based method for manually drawing a region of interest for the abdominal metastatic region was developed for monitoring tumor growth in orthotopic models of pancreatic cancer. The 2 region-of-interest methods were validated by having 2 observers independently segment Panc-1 tumors, and the results were compared with the number of mesenteric lymph node nodules and histopathologic assessment of liver metastases. The findings were extended to orthotopic tumors of the more metastatic MIA PaCa-2 and AsPC-1 cells where separate groups of animals were implanted with different numbers of cells. Results: The results demonstrated that the segmentation methods were highly reliable, reproducible, and robust and allowed statistically significant discrimination in the growth rates of primary and abdominal metastatic tumors of different cell lines implanted with different numbers of cells. Conclusions: The present results demonstrate that primary tumors and abdominal metastatic foci in orthotopic pancreatic cancer models can be reliably quantified separately and noninvasively over time with bioluminescence imaging.
APE1/Ref-1 knockdown in pancreatic ductal adenocarcinoma – characterizing gene expression changes and identifying novel pathways using single-cell RNA sequencing
(Wiley, 2017-12) Shah, Fenil; Goossens, Emery; Atallah, Nadia M.; Grimard, Michelle; Kelley, Mark R.; Fishel, Melissa L.; Department of Pediatrics, School of Medicine
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1 or APE1) is a multifunctional protein that regulates numerous transcription factors associated with cancer-related pathways. Because APE1 is essential for cell viability, generation of APE1-knockout cell lines and determining a comprehensive list of genes regulated by APE1 has not been possible. To circumvent this challenge, we utilized single-cell RNA sequencing to identify differentially expressed genes (DEGs) in relation to APE1 protein levels within the cell. Using a straightforward yet novel statistical design, we identified 2837 genes whose expression is significantly changed following APE1 knockdown. Using this gene expression profile, we identified multiple new pathways not previously linked to APE1, including the EIF2 signaling and mechanistic target of Rapamycin pathways and a number of mitochondrial-related pathways. We demonstrate that APE1 has an effect on modifying gene expression up to a threshold of APE1 expression, demonstrating that it is not necessary to completely knockout APE1 in cells to accurately study APE1 function. We validated the findings using a selection of the DEGs along with siRNA knockdown and qRT-PCR. Testing additional patient-derived pancreatic cancer cells reveals particular genes (ITGA1, TNFAIP2, COMMD7, RAB3D) that respond to APE1 knockdown similarly across all the cell lines. Furthermore, we verified that the redox function of APE1 was responsible for driving gene expression of mitochondrial genes such as PRDX5 and genes that are important for proliferation such as SIPA1 and RAB3D by treating with APE1 redox-specific inhibitor, APX3330. Our study identifies several novel genes and pathways affected by APE1, as well as tumor subtype specificity. These findings will allow for hypothesis-driven approaches to generate combination therapies using, for example, APE1 inhibitor APX3330 with other approved FDA drugs in an innovative manner for pancreatic and other cancer treatments.
Identification of new chemical entities targeting APE1 for the prevention of chemotherapy-induced peripheral neuropathy (CIPN)
(ASPET, 2016-01-01) Kelley, Mark R.; Wikel, James H.; Guo, Chunlu; Pollok, Karen E.; Bailey, Barbara J.; Wireman, Randy; Fishel, Melissa L.; Vasko, Michael R.; Department of Pediatrics, School of Medicine
Chemotherapy-induced peripheral neuropathy (CIPN) is a potentially debilitating side effect of a number of chemotherapeutic agents that does not have any FDA-approved interventions or prevention strategies. Although the cellular mechanisms mediating CIPN remain to be determined, several lines of evidence support the notion that DNA damage may be a causative factor in neuropathy induced by a number of cancer therapies. Therapies including platinum agents and ionizing radiation cause DNA damage in sensory neurons and augmenting key steps in the base excision repair (BER) pathway reverses this damage. Neuronal protection is provided by overexpressing APE1 as well as using a first generation targeted APE1 small molecule E3330 (also called APX3330). Accordingly, we determined whether novel second-generation APE1 targeted molecules would be protective against neurotoxicity-induced by cisplatin or oxaliplatin while not diminishing the anti-tumor effect of the platins. We determined using our ex vivo model of sensory neurons in culture measuring various endpoints of neurotoxicity that APX2009 is an effective small molecule that is neuroprotective against cisplatin and oxaliplatin-induced toxicity of sensory neurons. APX2009 also demonstrated a strong tumor cell killing effect in tumor cells. Additionally, the enhanced tumor cell killing was further shown in a more robust 3D pancreatic tumor model. Together, these data suggest that APX2009 is effective in preventing or reversing platinum-induced CIPN, while not affecting the anti-cancer activity of platins.
Ref-1/APE1 as Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia
(AACR, 2017-01-01) Ding, Jixin; Fishel, Melissa L.; Reed, April M.; McAdams, Erin; Czader, Magdalena; Cardoso, Angelo A.; Kelley, Mark R.; Department of Pediatrics, School of Medicine
The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets, but have yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pathways in T-ALL, we investigated the multi-functional protein redox factor-1 (Ref-1/APE1), which acts as a signaling "node" by exerting redox regulatory control of transcription factors important in leukemia. Leukemia patients' transcriptome databases showed increased expression in T-ALL of Ref-1 and other genes of the Ref-1/SET interactome. Validation studies demonstrated that Ref-1 is expressed in high-risk leukemia T-cells, including in patient biopsies. Ref-1 redox function is active in leukemia T-cells, regulating the Ref-1 target NF-kB, and inhibited by the redox-selective Ref-1 inhibitor E3330. Ref-1 expression is not regulated by Notch signaling, but is upregulated by glucocorticoid treatment. E3330 disrupted Ref-1 redox activity in functional studies and resulted in marked inhibition of leukemia cell viability, including T-ALL lines representing different genotypes and risk groups. Potent leukemia cell inhibition was seen in primary cells from ALL patients, relapsed and glucocorticoid-resistant T-ALL cells, and cells from a murine model of Notch-induced leukemia. Ref-1 redox inhibition triggered leukemia cell apoptosis and down-regulation of survival genes regulated by Ref-1 targets. For the first time, this work identifies Ref-1 as a novel molecular effector in T-ALL and demonstrates that Ref-1 redox inhibition results in potent inhibition of leukemia T-cells, including relapsed T-ALL. These data also support E3330 as a specific Ref-1 small molecule inhibitor for leukemia.
Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons
(Elsevier, 2016-05) Georgiadis, Millie M.; Chen, Qiujia; Meng, Jingwei; Guo, Chunlu; Wireman, Randall; Reed, April; Vasko, Michael R.; Kelley, Mark R.; Department of Biochemistry & Molecular Biology, IU School of Medicine
Although chemotherapy-induced peripheral neuropathy (CIPN) affects approximately 5-60% of cancer patients, there are currently no treatments available in part due to the fact that the underlying causes of CIPN are not well understood. One contributing factor in CIPN may be persistence of DNA lesions resulting from treatment with platinum-based agents such as cisplatin. In support of this hypothesis, overexpression of the base excision repair (BER) enzyme, apurinic/apyrimidinic endonuclease 1 (APE1), reduces DNA damage and protects cultured sensory neurons treated with cisplatin. Here, we address stimulation of APE1's endonuclease through a small molecule, nicorandil, as a means of mimicking the beneficial effects observed for overexpression of APE1. Nicorandil, was identified through high-throughput screening of small molecule libraries and found to stimulate APE1 endonuclease activity by increasing catalytic efficiency approximately 2-fold. This stimulation is primarily due to an increase in kcat. To prevent metabolism of nicorandil, an approved drug in Europe for the treatment of angina, cultured sensory neurons were pretreated with nicorandil and daidzin, an aldehyde dehydrogenase 2 inhibitor, resulting in decreased DNA damage but not altered transmitter release by cisplatin. This finding suggests that activation of APE1 by nicorandil in cisplatin-treated cultured sensory neurons does not imbalance the BER pathway in contrast to overexpression of the kinetically faster R177A APE1. Taken together, our results suggest that APE1 activators can be used to reduce DNA damage induced by cisplatin in cultured sensory neurons, although further studies will be required to fully assess their protective effects.
Challenges and opportunities identifying therapeutic targets for chemotherapy-induced peripheral neuropathy resulting from oxidative DNA damage
(Wolters Kluwer, 2017-01) Kelley, Mark R.; Fehrenbacher, Jill C.; Department of Pharmacology and Toxicology, IU School of Medicine
APE1, the DNA base excision repair protein, regulates the removal of platinum adducts in sensory neuronal cultures by NER
(Elsevier, 2015-09) Kim, Hyun-Suk; Guo, Chunlu; Jiang, Yanlin; Kelley, Mark R.; Vasko, Michael R.; Lee, Suk-Hee; Thompson, Eric L.; Department of Biochemistry & Molecular Biology, IU School of Medicine
Peripheral neuropathy is one of the major side effects of treatment with the anticancer drug, cisplatin. One proposed mechanism for this neurotoxicity is the formation of platinum adducts in sensory neurons that could contribute to DNA damage. Although this damage is largely repaired by nuclear excision repair (NER), our previous findings suggest that augmenting the base excision repair pathway (BER) by overexpressing the repair protein APE1 protects sensory neurons from cisplatin-induced neurotoxicity. The question remains whether APE1 contributes to the ability of the NER pathway to repair platinum-damage in neuronal cells. To examine this, we manipulated APE1 expression in sensory neuronal cultures and measured Pt-removal after exposure to cisplatin. When neuronal cultures were treated with increasing concentrations of cisplatin for two or three hours, there was a concentration-dependent increase in Pt-damage that peaked at four hours and returned to near baseline levels after 24h. In cultures where APE1 expression was reduced by ∼ 80% using siRNA directed at APE1, there was a significant inhibition of Pt-removal over eight hours which was reversed by overexpressing APE1 using a lentiviral construct for human wtAPE1. Overexpressing a mutant APE1 (C65 APE1), which only has DNA repair activity, but not its other significant redox-signaling function, mimicked the effects of wtAPE1. Overexpressing DNA repair activity mutant APE1 (226 + 177APE1), with only redox activity was ineffective suggesting it is the DNA repair function of APE1 and not its redox-signaling, that restores the Pt-damage removal. Together, these data provide the first evidence that a critical BER enzyme, APE1, helps regulate the NER pathway in the repair of cisplatin damage in sensory neurons.

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