Showing papers by "Peter Wipf published in 2015"

Ring-strain-enabled reaction discovery: new heterocycles from bicyclo[1.1.0]butanes.

Abstract: ConspectusMechanistically as well as synthetically, bicyclo[1.1.0]butanes represent one of the most fascinating classes of organic compounds. They offer a unique blend of compact size (four carbon atoms), high reactivity (strain energy of 66 kcal/mol), and mechanistic pathway diversity that can be harvested for the rapid assembly of complex scaffolds. The C(1)–C(3) bond combines the electronic features of both σ and π bonds with facile homolytic and heterolytic bond dissociation properties and thereby readily engages pericyclic, transition-metal-mediated, nucleophilic, and electrophilic pathways as well as radical acceptor and donor substrates.Despite this multifaceted reaction profile and recent advances in the preparation of bicylo[1.1.0]butanes, the current portfolio of synthetic applications is still limited compared with those of cyclopropanes and cyclobutanes. In this Account, we describe our work over the past decade on the exploration of substituent effects on the ring strain and the reactivity of...

Deciphering of mitochondrial cardiolipin oxidative signaling in cerebral ischemia-reperfusion.

Abstract: It is believed that biosynthesis of lipid mediators in the central nervous system after cerebral ischemia-reperfusion starts with phospholipid hydrolysis by calcium-dependent phospholipases and is followed by oxygenation of released fatty acids (FAs). Here, we report an alternative pathway whereby cereberal ischemia-reperfusion triggered oxygenation of a mitochondria-specific phospholipid, cardiolipin (CL), is followed by its hydrolysis to yield monolyso-CLs and oxygenated derivatives of fatty (linoleic) acids. We used a model of global cerebral ischemia-reperfusion characterized by 9 minutes of asphyxia leading to asystole followed by cardiopulmonary resuscitation in postnatal day 17 rats. Global ischemia and cardiopulmonary resuscitation resulted in: (1) selective oxidation and hydrolysis of CLs, (2) accumulation of lyso-CLs and oxygenated free FAs, (3) activation of caspase 3/7 in the brain, and (4) motor and cognitive dysfunction. On the basis of these findings, we used a mitochondria targeted nitroxide electron scavenger, which prevented CL oxidation and subsequent hydrolysis, attenuated caspase activation, and improved neurocognitive outcome when administered after cardiac arrest. These data show that calcium-independent CL oxidation and subsequent hydrolysis represent a previously unidentified pathogenic mechanism of brain injury incurred by ischemia-reperfusion and a clinically relevant therapeutic target.

Structure-Activity Study of Bioisosteric Trifluoromethyl and Pentafluorosulfanyl Indole Inhibitors of the AAA ATPase p97.

Abstract: Exploratory SAR studies of a new phenyl indole chemotype for p97 inhibition revealed C-5 indole substituent effects in the ADPGlo assay that did not fully correlate with either electronic or steric factors. A focused series of methoxy-, trifluoromethoxy-, methyl-, trifluoromethyl-, pentafluorosulfanyl-, and nitro-analogues was found to exhibit IC50s from low nanomolar to double-digit micromolar. Surprisingly, we found that the trifluoromethoxy-analogue was biochemically a better match of the trifluoromethyl-substituted lead structure than a pentafluorosulfanyl-analogue. Moreover, in spite of their almost equivalent strongly electron-depleting effect on the indole core, pentafluorosulfanyl- and nitro-derivatives were found to exhibit a 430-fold difference in p97 inhibitory activities. Conversely, the electronically divergent C-5 methyl- and nitro-analogues both showed low nanomolar activities.

Mitochondria-targeted antioxidant preserves contractile properties and mitochondrial function of skeletal muscle in aged rats

Abstract: Mitochondrial dysfunction plays a central role in the pathogenesis of sarcopenia associated with a loss of mass and activity of skeletal muscle. In addition to energy deprivation, increased mitochondrial ROS damage proteins and lipids in aged skeletal muscle. Therefore, prevention of mitochondrial ROS is important for potential therapeutic strategies to delay sarcopenia. This study elucidates the pharmacological efficiency of the new developed mitochondria-targeted ROS and electron scavenger, XJB-5-131 (XJB) to restore muscle contractility and mitochondrial function in aged skeletal muscle. Male adult (5-month old) and aged (29-month old) Fischer Brown Norway (F344/BN) rats were treated with XJB for four weeks and contractile properties of single skeletal muscle fibres and activity of mitochondrial ETC complexes were determined at the end of the treatment period. XJB-treated old rats showed higher muscle contractility associated with prevention of protein oxidation in both muscle homogenate and mitochondria compared with untreated counterparts. XJB-treated animals demonstrated a high activity of the respiratory complexes I, III, and IV with no changes in citrate synthase activity. These data demonstrate that mitochondrial ROS play a causal role in muscle weakness, and that a ROS scavenger specifically targeted to mitochondria can reverse age-related alterations of mitochondrial function and improve contractile properties in skeletal muscle.

SD-208, a novel protein kinase D inhibitor, blocks prostate cancer cell proliferation and tumor Growth in Vivo by inducing G2/M cell cycle arrest

Abstract: Protein kinase D (PKD) has been implicated in many aspects of tumorigenesis and progression, and is an emerging molecular target for the development of anticancer therapy. Despite recent advancement in the development of potent and selective PKD small molecule inhibitors, the availability of in vivo active PKD inhibitors remains sparse. In this study, we describe the discovery of a novel PKD small molecule inhibitor, SD-208, from a targeted kinase inhibitor library screen, and the synthesis of a series of analogs to probe the structure-activity relationship (SAR) vs. PKD1. SD-208 displayed a narrow SAR profile, was an ATP-competitive pan-PKD inhibitor with low nanomolar potency and was cell active. Targeted inhibition of PKD by SD-208 resulted in potent inhibition of cell proliferation, an effect that could be reversed by overexpressed PKD1 or PKD3. SD-208 also blocked prostate cancer cell survival and invasion, and arrested cells in the G2/M phase of the cell cycle. Mechanistically, SD-208-induced G2/M arrest was accompanied by an increase in levels of p21 in DU145 and PC3 cells as well as elevated phosphorylation of Cdc2 and Cdc25C in DU145 cells. Most importantly, SD-208 given orally for 24 days significantly abrogated the growth of PC3 subcutaneous tumor xenografts in nude mice, which was accompanied by reduced proliferation and increased apoptosis and decreased expression of PKD biomarkers including survivin and Bcl-xL. Our study has identified SD-208 as a novel efficacious PKD small molecule inhibitor, demonstrating the therapeutic potential of targeted inhibition of PKD for prostate cancer treatment.

Synaptic Pathophysiology and Treatment of Lambert-Eaton Myasthenic Syndrome.

Abstract: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that disrupts the normally reliable neurotransmission at the neuromuscular junction (NMJ). This disruption is thought to result from an autoantibody-mediated removal of a subset of the P/Q-type Ca(2+) channels involved with neurotransmitter release. With less neurotransmitter release at the NMJ, LEMS patients experience debilitating muscle weakness. The underlying cause of LEMS in slightly more than half of all patients is small cell lung cancer, and cancer therapy is the priority for these patients. In the remaining cases, the cause of LEMS is unknown, and these patients often rely on symptomatic treatment options, as there is no cure. However, current symptomatic treatment options, such as 3,4-diaminopyridine (3,4-DAP), can have significant dose-limiting side effects; thus, additional treatment approaches would benefit LEMS patients. Recent studies introduced a novel Ca(2+) channel agonist (GV-58) as a potential therapeutic alternative for LEMS. Additionally, this work has shown that GV-58 and 3,4-DAP interact in a supra-additive manner to completely restore the magnitude of neurotransmitter release at the NMJs of a LEMS mouse model. In this review, we discuss synaptic mechanisms for reliability at the NMJ and how these mechanisms are disrupted in LEMS. We then discuss the current treatment options for LEMS patients, while also considering recent work demonstrating the therapeutic potential of GV-58 alone and in combination with 3,4-DAP.

HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

Abstract: Signal transducer and activator of transcription factor 3 (STAT3) is hyperactivated in head and neck squamous cell carcinomas (HNSCC). Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network (MLSCN) was screened for the ability to inhibit interleukin-6 (IL-6)-induced pSTAT3 activation. For contractual reasons, the primary high-content screening (HCS) campaign was conducted over several months in 3 distinct phases; 1,068 (1.1%) primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton.

The cytotoxic effects of regorafenib in combination with protein kinase D inhibition in human colorectal cancer cells.

Abstract: // Ning Wei 1,2 , Edward Chu 1,2 , Shao-yu Wu 1,2 , Peter Wipf 2,3 and John C. Schmitz 1,2 1 Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 2 Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA 3 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA Correspondence: Ning Wei, email: // Keywords : protein kinase D, regorafenib, human colorectal cancer, apoptosis, NF-κB Received : August 12, 2014 Accepted : December 02, 2014 Published : December 03, 2014 Abstract Metastatic colorectal cancer (mCRC) remains a major public health problem, and diagnosis of metastatic disease is usually associated with poor prognosis. The multi-kinase inhibitor regorafenib was approved in 2013 in the U.S. for the treatment of mCRC patients who progressed after standard therapies. However, the clinical efficacy of regorafenib is quite limited. One potential strategy to improve mCRC therapy is to combine agents that target key cellular signaling pathways, which may lead to synergistic enhancement of antitumor efficacy and overcome cellular drug resistance. Protein kinase D (PKD), a family of serine/threonine kinases, mediates key signaling pathways implicated in multiple cellular processes. Herein, we evaluated the combination of regorafenib with a PKD inhibitor in several human CRC cells. Using the Chou-Talalay model, the combination index values for this combination treatment demonstrated synergistic effects on inhibition of cell proliferation and clonal formation. This drug combination resulted in induction of apoptosis as determined by flow cytometry, increased PARP cleavage, and decreased activation of the anti-apoptotic protein HSP27. This combination also yielded enhanced inhibition of ERK, AKT, and NF-κB signaling. Taken together, PKD inhibition in combination with regorafenib appears to be a promising strategy for the treatment of mCRC.

Chapter 11 – Conformational Restriction and Steric Hindrance in Medicinal Chemistry

Abstract: Strategies to impact the biomolecular recognition of small molecules by attenuating steric bulk and conformational restriction are addressed. Specific examples include atropisomers, peptidomimetics, methyl group effects, and the application of diversity-oriented synthesis.

Antioxidant Approaches to Management of Ionizing Irradiation Injury

Abstract: Ionizing irradiation induces acute and chronic injury to tissues and organs. Applications of antioxidant therapies for the management of ionizing irradiation injury fall into three categories: (1) radiation counter measures against total or partial body irradiation; (2) normal tissue protection against acute organ specific ionizing irradiation injury; and (3) prevention of chronic/late radiation tissue and organ injury. The development of antioxidant therapies to ameliorate ionizing irradiation injury began with initial studies on gene therapy using Manganese Superoxide Dismutase (MnSOD) transgene approaches and evolved into applications of small molecule radiation protectors and mitigators. The understanding of the multiple steps in ionizing radiation-induced cellular, tissue, and organ injury, as well as total body effects is required to optimize the use of antioxidant therapies, and to sequence such approaches with targeted therapies for the multiple steps in the irradiation damage response.

Heat shock protein responses to aging and proteotoxicity in the olfactory bulb

Abstract: The olfactory bulb is one of the most vulnerable brain regions in age-related proteinopathies. Proteinopathic stress is mitigated by the heat shock protein (Hsp) family of chaperones. Here, we describe age-related decreases in Hsc70 in the olfactory bulb of the female rat and higher levels of Hsp70 and Hsp25 in middle and old age than at 2-4 months. To model proteotoxic and oxidative stress in the olfactory bulb, primary olfactory bulb cultures were treated with the proteasome inhibitors lactacystin and MG132 or the pro-oxidant paraquat. Toxin-induced increases were observed in Hsp70, Hsp25, and Hsp32. To determine the functional consequences of the increase in Hsp70, we attenuated Hsp70 activity with two mechanistically distinct inhibitors. The Hsp70 inhibitors greatly potentiated the toxicity of sublethal lactacystin or MG132 but not of paraquat. Although ubiquitinated protein levels were unchanged with aging in vivo or with sublethal MG132 in vitro, there was a large, synergistic increase in ubiquitinated proteins when proteasome and Hsp70 functions were simultaneously inhibited. Our study suggests that olfactory bulb cells rely heavily on Hsp70 chaperones to maintain homeostasis during mild proteotoxic, but not oxidative insults, and that Hsp70 prevents the accrual of ubiquitinated proteins in these cells. The olfactory bulb is affected in the early phases of many age-related neurodegenerative disorders. Here, we described the impact of aging on multiple heat shock proteins (Hsps), such as Hsp70, in the female rat olfactory bulb in vivo. Using multiple proteasome and Hsp70 inhibitors (see schematic), we found that proteotoxicity elicited a compensatory increase in Hsp70 in primary olfactory bulb cells in vitro. Hsp70 then reduced the proteotoxic buildup of ubiquitinated proteins and robustly protected against cell death according to three independent viability assays. Thus, olfactory bulb neurons can mount impressive natural adaptations to proteotoxic injury, perhaps explaining why neurodegenerative disorders are so delayed in onset and so slow to progress.

Bis-cyclopropane analog of disorazole C 1 is a microtubule-destabilizing agent active in ABCB1-overexpressing human colon cancer cells

Abstract: // Shaoyu Wu 1, 2, 3 , Zhijian Guo 4 , Chad D. Hopkins 5 , Ning Wei 1, 2 , Edward Chu 1, 2 , Peter Wipf 2, 5 , John C. Schmitz 1, 2 1 Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA 2 Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA 3 Department of Chemistry, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, China 4 Department of Nephrology, NanFang Hospital, Southern Medical University, Guangzhou 510515, China 5 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA Correspondence to: John C. Schmitz, e-mail: schmitzjc@upmc.edu Keywords: tubulin polymerization, disorazole, human colorectal cancer Received: July 15, 2015 Accepted: September 28, 2015 Published: October 19, 2015 ABSTRACT The novel, chemically stabilized disorazole analog, (-)-CP 2 -disorazole C 1 ( 1 ) displayed potent anti-proliferative activity against a broad-spectrum of human colorectal cancer cells. HCT15 and H630R1 cell lines expressing high basal levels of the ABCB1 protein, known to cause multi-drug resistance, were also sensitive to growth inhibition by 1 but were resistant to both vincristine and docetaxel, two commonly used microtubule inhibitors. Compound 1 exhibited strong inhibition of tubulin polymerization at a level comparable to vincristine. In addition, treatment with 1 resulted in decreased protein levels of β-tubulin but not α-tubulin. An analysis of cellular proteins known to interact with microtubules showed that 1 caused decreased expression of c-Myc, APC, Rb, and additional key cellular signaling pathways in CRC cells. Treatment with compound 1 also resulted in G2/M cell cycle arrest and induction of apoptosis, but not senescence. Furthermore, endothelial spheroid sprouting assays demonstrated that 1 suppressed angiogenesis and can, therefore, potentially prevent cancer cells from spreading and metastasizing. Taken together, these findings suggest that the microtubule disruptor 1 may be a potential drug candidate for the treatment of mCRC.

Novel tlr4 inhibitors for the treatment of human infectious and inflammatory disorders

Abstract: The present invention relates to methods of treating infectious, inflammatory and post-traumatic disorders by administering various compounds newly discovered to have TLR4 inhibitory activity. In addition to methods of treatment, the present invention further provides for pharmaceutical compositions comprising said compounds, together with a suitable pharmaceutical carrier. Because TLR4 is the most upstream receptor in the pro-inflammatory LPS signaling cascade, treatments of the invention, which inhibit or antagonize TLR4 action, may avoid the pitfalls associated with other cytokine inhibitors that act further down the pathway and accordingly play a less specific (and perhaps non-critical) role.

The Effect of Structure and Mechanism of the Hsp70 Chaperone on the Ability to Identify Chemical Modulators and Therapeutics

Abstract: The role of the Hsp70 molecular chaperone in effecting proper cellular protein folding, transport, and degradation processes, stabilizing protein complexes, and maintaining membrane integrity has long been recognized. More recently, Hsp70 has been linked to severe neurological diseases, such as Alzheimer’s, Parkinson’s and Huntington’s disease, as well as to cystic fibrosis and cancer. As a result, there is a growing interest in the development of small-molecule modulators of Hsp70 function. While several distinct classes of Hsp70 agonists and antagonists have been identified to date, clinical studies with Hsp70-targeted drugs have yet to be initiated, and proof of principle for therapeutic benefits remains to be established. However, a large body of preclinical biological evidence suggests that this chaperone plays a key role in many human diseases associated with protein (un)folding and trafficking and that the continued development of Hsp70 modulators will yield novel therapeutic strategies.

Ring‐Strain‐Enabled Reaction Discovery: New Heterocycles from Bicyclo[1.1.0]butanes

Abstract: ConspectusMechanistically as well as synthetically, bicyclo[1.1.0]butanes represent one of the most fascinating classes of organic compounds. They offer a unique blend of compact size (four carbon atoms), high reactivity (strain energy of 66 kcal/mol), and mechanistic pathway diversity that can be harvested for the rapid assembly of complex scaffolds. The C(1)–C(3) bond combines the electronic features of both σ and π bonds with facile homolytic and heterolytic bond dissociation properties and thereby readily engages pericyclic, transition-metal-mediated, nucleophilic, and electrophilic pathways as well as radical acceptor and donor substrates.Despite this multifaceted reaction profile and recent advances in the preparation of bicylo[1.1.0]butanes, the current portfolio of synthetic applications is still limited compared with those of cyclopropanes and cyclobutanes. In this Account, we describe our work over the past decade on the exploration of substituent effects on the ring strain and the reactivity of...

(2-amino-4(arylamino)phenyl) carbamates

Abstract: A compound, or pharmaceutically acceptable salt thereof, having a formula I of: wherein R 1 is H or optionally-substituted alkyl; R 2 is optionally-substituted alkyl; R 3 and R 4 are each independently H or optionally-substituted alkyl; R 5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R 6 and R 7 are each independently H, deuterium, optionally-substituted alkyl, or R 6 and R 7 together form a carbocyclic; R 8 is optionally-substituted thiazolyl, optionally-substituted thiophenyl, or substituted phenyl, provided that if R 8 is 4-halophenyl, then R 2 is substituted alkyl or branched alkyl or at least one of R 6 or R 7 is not H; and R 30 , R 31 and R 32 are each independently H, deuterium, halogen, substituted sulfanyl, or optionally-substituted alkoxy.

Abstract 3340: Intraoral administration of mitochondrial targeted GS-nitroxide (JP4-039) radioprotects the oral mucosa but not orthotopic tumors in Fancd2-/- mice

Abstract: Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Fanconi Anemia (FA) patients are at risk for head and neck squamous cell carcinomas. Their normal tissue radiosensitivity often presents a challenge to deliver radiotherapy. Locally applied GS-nitroxide JP4-039 radioprotects the oral mucosa of Fancd2-/-(129/Sv) mice from single fraction or fractionated irradiation (Berhane et al, Radiation Research 182:35-49, 2014). We sought to prove that JP4-039 targets the mitochondria of the oral mucosal cells, and protects normal tissue in vivo, but does not prevent radiocontrolability of tumors. Fancd2+/+, Fancd2+/- and Fancd2-/- mice of a different background strain (C57BL/6), received intraoral flurochrome labelled bodipy-JP4-039 in F15 liposomes, were sacrificed 2 hr later and the oral mucosa removed sectioned, and stained with an antibody to mitochondrial protein TOM-20 and examined microscopically for co-localization of bodipy-JP4-039. Mitochondria were isolated from explanted oral mucosal cells and uptake of JP4-039 compared to non-mitochondrial targeted Tempo, measured using EPR. Fancd2+/+, Fancd2+/- and Fancd2-/- mice with orthotopic TC-1 murine squamous cell tumors were treated with JP-4-039/F15, then irradiated. Mitochondrial uptake in normal tissue but not tumors was demonstrated by co-localization of Bodipy-JP4-039 and mitochondrial protein TOM-20. EPR analysis of purified mitochondria from explanted oral cavity cells of Fancd2+/+ and Fancd2-/- mice treated with F15-JP4-039 showed a 15.6 and 19.1 fold increased uptake of nitroxide signal in JP4-039 treated mice, respectively, compared to Tempo uptake in mitochondria . There was no significant difference in tumor control between the JP4-039/F15 treated then irradiated compared to control irradiated mice, in any of the 3 genotypes: Fancd2+/+ group, p = 0.6851; Fancd2+/− group p = 0.7174 and p = 0.7559 in the Fancd2−/− group. JP4-039/F15 administration prior to either single fraction 28 Gy or prior to each fraction of fractionated head and neck irradiation (8 Gy x 4) showed significant normal tissue protection (decreased ulceration) but not tumor radioprotection. Irradiation reduced tumor volume in mice of all genotypes with no detectable effect of JP4-039/F15. Specifically, with wild type Fancd2+/+ mice after 28 Gy, there was no radioprotective effect of JP4-039/F15 on tumor regrowth (p = 0.7520). Tumor bearing Fancd2−/− (p = 0.1843) and Fancd2+/− mice also showed normal tissue but not tumor protection (p = 0.4106 and p = 0.1843, respectively). The data support use of normal mucosal radioprotective JP4-039/F15 during radiotherapy of FA patients with head and neck cancer. Citation Format: Michael W. Epperly, Ashwin Shinde, Hebist Berhane, Byung Han Rhieu, Ronny Kalash, Karen Xu, Darcy Franicola, Xichen Zhang, Tracy Dixon, Donna Shields, Hong Wang, Peter Wipf, Kalindi Parmar, Eva Guinan, Valerian Kagan, Yulia Tyurina, Robert L. Ferris, Song Li, Joel S. Greenberger. Intraoral administration of mitochondrial targeted GS-nitroxide (JP4-039) radioprotects the oral mucosa but not orthotopic tumors in Fancd2-/- mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3340. doi:10.1158/1538-7445.AM2015-3340

Gene Therapy for Mucositis

Abstract: A major dose limiting toxicity of chemoradiotherapy of head and neck cancer is mucositis. Attempts to decrease radiation damage have included both locally delivered and systemic strategies. A highly effective locally applied radioprotectant is Manganese Superoxide Dismutase-Plasmid Liposomes (MnSOD-PL), which has been shown in animal models with fractionated radiotherapy to the head and neck to be an effective radioprotector, when delivered between each radiotherapy fraction. Intraoral administration of Manganese Superoxide Dismutase-Plasmid Liposomes (MnSOD-PL) prior to single fraction irradiation or immediately before each of multiple fractions of head and neck irradiation significantly reduces oral cavity and oropharyngeal mucositis in the C57BL/6NHsd model. The mechanism is dependent upon mitochondrial targeting of the MnSOD transgene product. A phase I Clinical Trial of administration of MnSOD-PL to patients twice a week during chemoradiotherapy of lung cancer has demonstrated significant protection of the esophagus in patients, who swallow MnSOD-PL. A “mouthwash” administration of MnSOD-PL is being tested in a clinical trial at the University of Pittsburgh Cancer Institute. Reduction of irradiation-induced oral cavity and oropharyngeal mucositis should allow dose escalation in clinical trials of chemoradiotherapy and biological response modifier therapy of head and neck cancers, but more importantly, reduce significant side effects of treatment. An attractive evolution of this gene therapy approach has been the development of small molecule radioprotectants, prominently mitochondrial targeted 4-amino tempo. Mitochondrial targeting has been optimized with the development of hemigramicidin linkers, which deliver concentrated drug to the mitochondria thereby limiting radiation-induced apoptosis. The GS-nitroxide, JP4-039, then delivered in a novel F15 tissue targeted emulsion provides significant radioprotection of normal oral cavity and oropharyngeal mucosa when delivered before single fraction or between fractions of radiotherapy. The ease of administration of oral cavity/oropharynx radioprotectants makes their application in clinical translational protocols both safe and feasible.

Combination therapy to enhance the anticancer efficacy of platinum drugs

Abstract: The present invention relates to compositions and methods for reducing cell proliferation and/or promoting cell death. It is based, at least in part, on the discovery that in platinum drug-resistant cell lines, certain compounds, together with a second antiproliferative agent (e.g., cisplatin), act synergistically to promote apoptosis. Accordingly, the present invention provides for novel anticancer strategies.