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Background Personalized cancer immunotherapies can generate potent antitumor responses yet finding the right targets remains challenging. The ATLASTM platform employs ex vivo functional screening of tumor mutations using autologous cells to identify patient-specific neoantigens. Stimulatory neoantigens are identified by upregulation of inflammatory cytokine secretion and can be employed in vaccines or cell therapies. Conversely, ATLAS also identifies inhibitory neoantigens (termed Inhibigens) that lead to cytokine downregulation, and in murine models accelerate tumor growth and abrogate the efficacy of otherwise-protective vaccines. Here we further explore Inhibigen mechanism of action in humans and mice including whether checkpoint inhibition (CPI) can ameliorate Inhibigen-accelerated tumor growth. Methods Human and mouse ATLAS screens were performed as previously described.1 ATLAS-identified stimulatory or Inhibigen peptide vaccines were evaluated in a therapeutic B16F10 melanoma tumor model ± CPI. Immune responses were measured using ELISPOT, flow cytometry, and immunohistochemistry (IHC). Results In the GEN-009 personalized neoantigen vaccine trial (NCT03633110), Inhibigens were observed in 92% of patients (N=39). Of total mutations screened, 16% (1.8 - 47.5%) were classified as Inhibigens, which were found more often in the CD4 + (mean 10.3%; 0.5 - 42%) versus CD8 + T cell subset (mean 6.1%; 1.2–23%). No relationship between Inhibigen-specific responses and tumor type or mutational burden were observed. To study the functional effects of Inhibigen vaccination in vivo, a B16F10 mouse melanoma model was employed. Inclusion of Inhibigens in an otherwise protective vaccine abrogated efficacy and correlated with decreased T cell responses to vaccine antigens as well as a global depression of T cell cytokine secretion. Early experiments suggest that these decreases are not due to MHC competition. In addition, administration of a therapeutic vaccine containing an Inhibigen led to reduced tumor infiltration of CD8 + T cells and myeloid populations. A corresponding increase of classical Tregs in the tumor or periphery was not observed. Surprisingly, preliminary data show combination therapy with anti-CTLA4 partially ameliorated Inhibigen-accelerated tumor growth but anti-PD1 provided no additional benefit. Conclusions The nearly ubiquitous presence of Inhibigens in human cancer patients and the demonstrated pro-tumor effects in mice suggest that ATLAS-identified Inhibigens must be considered and omitted in the design of cancer immunotherapies. Furthermore, in mice, CPI co-administration has a modest (anti-CTLA4) or no (anti-PD1) effect on Inhibigen-accelerated tumor growth suggesting that Inhibigen profiling could guide CPI selection or predict clinical outcome. These data confirm the benefits of the ATLAS platform for neoantigen and Inhibigen identification. Ethics Approval All animal studies were undertaken in conformity with the Cambridge, MA City Ordinance 1086 of the city’s Municipal Code and in accordance with the policies and protocols approved by Genocea’s Institutional Animal Care and Use Committee (IACUC). Reference Nogueira C, Kaufmann JK, Lam H, Flechtner JB. Improving cancer immunotherapies through empirical neoantigen selection. Trends in Cancer 2018 Feb;4(2):97–100

NAD, a key co-enzyme required for cell metabolism, is synthesized via two pathways in most organisms. Since schistosomes apparently lack enzymes required for de novo NAD biosynthesis, we evaluated whether these parasites, which infect >200 million people worldwide, maintain NAD homeostasis via the NAD salvage biosynthetic pathway. We found that intracellular NAD levels decline in schistosomes treated with drugs that block production of nicotinamide or nicotinamide mononucleotide–known NAD precursors in the non-deamidating salvage pathway. Moreover, in vitro inhibition of the NAD salvage pathway in schistosomes impaired egg production, disrupted the outer membranes of both immature and mature parasites and caused loss of mobility and death. Inhibiting the NAD salvage pathway in schistosome-infected mice significantly decreased NAD levels in adult parasites, which correlated with reduced egg production, fewer liver granulomas and parasite death. Thus, schistosomes, unlike their mammalian hosts, appear limited to one metabolic pathway to maintain NAD-dependent metabolic processes., Author summary Schistosomiasis (snail fever) is a deadly parasitic disease that affects more than 200 million people worldwide and, if not treated, can lead to death. This disease is caused by parasitic worms called schistosomes that feed on the host blood and lay hundreds of eggs each day that damage the liver and kidneys. Therapies to treat schistosomiasis are limited. The most widely-used anti-schistosomal drug, praziquantel, is not effective against immature parasites and adult worms can, in some cases, become resistant to this drug. It is therefore important to find new therapies to treat this deadly disease. In this study, we observed that schistosomes cannot use amino acids to make Nicotinamide Adenine Dinucleotide (NAD)–a key cellular metabolite found in all living organisms. Instead, these parasites salvage NAD by scavenging vitamins from the host. We observed that disruption of this NAD salvage pathway negatively impacts metabolism, reproduction and survival of both adult and immature worms. As such, targeting the parasite’s NAD salvage pathway is a promising therapeutic approach for the treatment of snail fever.

BackgroundEffective immune checkpoint blockade (ICB) treatment is dependent on T-cell recognition of patient-specific mutations (neoantigens). Empirical identification of neoantigens ex vivo has revealed shortcomings of in silico predictions.1 To better understand the impact of ICB treatment on T cell responses and differences between in silico and in vitro methods, neoantigen-specific T cell responses were evaluated in patients with non-small cell lung cancer undergoing first-line therapy with pembrolizumab ± chemotherapy.MethodsTumor and whole blood samples were collected from 14 patients prior to and after immunotherapy; seven each in monotherapy and combination therapy cohorts. The ex vivo ATLAS™ platform was used to profile neoantigen-specific T-cell responses. Patient-specific tumor mutations identified by next-generation sequencing (NGS) were expressed individually as ATLAS clones, processed patient-specific autologous antigen presenting cells, and presented to their T cells in vitro. ATLAS-verified antigens were compared with epitope predictions made using algorithms.ResultsOn average, 150 (range 37–339) non-synonymous mutations were identified. Pre-treatment, ATLAS identified T cell responses to a median of 15% (9–25%) of mutations, with nearly equal proportions of neoantigens (8%, 5–15%) and Inhibigens™, targets of suppressive T cell responses (8%, 3–13%). The combination therapy cohort had more confirmed neoantigens (46, 20–103) than the monotherapy cohort (7, 6–79). After treatment, the median ratio of CD4:CD8 T cells doubled in the monotherapy but not combination cohort (1.2 to 2.4 v. 1.6 to 1.3). Upon non-specific stimulation, T cells from patients on combination therapy expanded poorly relative to monotherapy (24 v. 65-fold, p = 0.014); no significant differences were observed pre-treatment (22 v. 18-fold, p = 0.1578). Post-treatment, the median number of CD8 neoantigens increased in the combination therapy cohort (11 to 15) but in monotherapy were mostly unchanged (6 to 7). Across timepoints, 36% of ATLAS-identified responses overlapped. In silico analysis resulted in 1,895 predicted epitopes among 961 total mutations; among those, 30% were confirmed with ATLAS, although nearly half were Inhibigens, which could not be predicted. Moreover, 50% of confirmed neoantigens were missed by in silico prediction.ConclusionsMonotherapy and combination therapy had differential effects on CD4:CD8 T cell ratios and their non-specific expansion. A greater proportion of neoantigens was identified than previously reported in studies employing in silico predictions prior to empirical verification.2 Overlap between confirmed antigens and in silico prediction was observed, but in silico prediction continued to have a large false negative rate and could not characterize Inhibigens.AcknowledgementsWe would like to acknowledge and thank the patients and their families for participating in this study.ReferencesLam H, McNeil LK, Starobinets H, DeVault VL, Cohen RB, Twardowski P, Johnson ML, Gillison ML, Stein MN, Vaishampayan UN, DeCillis AP, Foti JJ, Vemulapalli V, Tjon E, Ferber K, DeOliveira DB, Broom W, Agnihotri P, Jaffee EM, Wong KK, Drake CG, Carroll PM, Davis TA, Flechtner JB. An empirical antigen selection method identifies neoantigens that either elicit broad antitumor T-cell responses or drive tumor growth. Cancer Discov 2021;11(3):696–713. doi: 10.1158/2159- 8290.CD-20-0377. Epub 2021 January 27. PMID: 33504579. Rosenberg SA. Immersion in the search for effective cancer immunotherapies. Mol Med 27,63(2021). https://doi.org/10.1186/s10020-021-00321-3

Objective Alzheimer's disease (AD)-associated dementia is due to tissue damage caused by amyloid β (Aβ) deposition within the brain and by accompanying neuroinflammation. The nicotinamide adenine dinucleotide (NAD) glycohydrolase CD38, which is expressed by neurons, astrocytes, and microglial cells, regulates inflammatory and repair processes in the brain and other tissues by degrading NAD and repressing the activity of other NAD-consuming enzymes and by producing NAD-derived metabolites that regulate calcium signaling and migration of inflammatory cells. Given the role of CD38 in neuroinflammation and repair, we examined the effect of CD38 deletion on AD pathology. Methods We crossed APPswePS1ΔE9 (APP.PS) mice with Cd38(-) (/) (-) mice to generate AD-prone CD38-deficient animals (APP.PS.Cd38(-) (/) (-) ) and examined AD-related phenotypes in both groups. Results APP.PS.Cd38(-) (/) (-) mice exhibited significant reductions in Aβ plaque load and soluble Aβ levels compared to APP.PS mice, and this correlated with improved spatial learning. Although CD38 deficiency resulted in decreased microglia/macrophage (MM) accumulation, the transcription profile of the Cd38(-) (/) (-) and Cd38(+/) (+) MM was similar, suggesting that the decreased Aβ burden in APP.PS.Cd38(-) (/) (-) mice was not due to alterations in MM activation/function. Instead, APP.PS.Cd38(-) (/) (-) neuronal cultures secreted less Aβ and this reduction was mimicked when APP.PS neuronal cultures were treated with inhibitors that blocked CD38 enzyme activity or the signaling pathways controlled by CD38-derived metabolites. Furthermore, β- and γ-secretase activity was decreased in APP.PS.Cd38(-) (/) (-) mice, which correlated with decreased Aβ production. Interpretation CD38 regulates AD pathology in the APP.PS model of AD, suggesting that CD38 may be a novel target for AD treatment.

To investigate the efficacy of endocrine parathyroid hormone treatment on tissue-engineered bone regeneration, massive femoral defects in C57Bl/6 mice were reconstructed with either 100:0 or 85:15 poly-lactic acid (PLA)/beta-tricalcium phosphate (β-TCP) scaffolds (hereafter PLA or PLA/βTCP, respectively), which were fabricated with low porosity (

Mitochondria play a multifaceted role in tumorigenesis through regulation of energy production, biomass, redox state, and engagement of cell death pathways. The mitochondrial Q (coenzyme Q10)-pool facilitates electron transport from Complexes I and II to III and is essential for regulating these activities. Therefore, altering mitochondrial Q-pool homeostasis represents a potential therapeutic strategy in cancer. BPM 31510 is a Coenzyme Q10 containing lipid nanodispersion currently in clinical trials for pancreatic cancer. Here, we used BPM 31510 to assess how modulation of mitochondrial Q-pool homeostasis impacts mitochondrial electron transport chain function to activate regulated cell death. Pancreatic cancer cell lines (MIA PaCa-2 and Panc-1) represent models with sensitivity to BPM 31510 both in vitro and in vivo. Treatment with BPM 31510 (EC50 dose, 24 h) resulted in significant mitochondrial enrichment of CoQ10 compared to other subcellular compartments, and quantitatively, CoQ10 levels were 100 times higher in mitochondria isolated from BPM 31510 treated cells over untreated controls (MIA PaCa-2 untreated, 0.31 nmol/mg; treated, 39.4 nmol/mg; Panc1 untreated, 0.21 nmol/mg; treated, 29.3 nmol/mg). Alterations in mitochondrial respiration characterized by dose-dependent decreases in succinate- or glycerol-3-phosphate-fueled respiration were observed in cells treated with BPM 31510, while pyruvate or TMPD/ascorbate-fueled respiration was only modestly affected, suggesting that BPM31510 specifically impairs respiratory responses dependent on Complexes II/III. Moreover, in the presence of multiple mitochondrial substrates, total respiratory capacity was decreased and reliance on pyruvate (Complex I)-fueled respiration was increased with BPM 31510 treatment, indicative of bioenergetic remodeling. Concomitantly to BPM 31510-dependent changes in mitochondrial respiratory responses, BPM 31510 exposure increased oxidation of the reactive oxygen species (ROS) probes, CellROX Green and DCF-DA, increased oxidized glutathione, and decreased levels of the cellular reducing equivalent NADPH. Importantly, BPM 31510-induced death could be partially rescued by agents which alleviate electron transport chain impairment linking respiratory function to the anti-cancer mechanism of action of BPM 31510. Together, these data indicate that BPM31510 directly impairs the mitochondrial Q-pool and respiratory function resulting in oxidative stress and consequential cell death and thus provide mechanistic understanding of the anti-cancer activity of BPM31510. Citation Format: Pallavi Awate, Tulin Dadali, Ryan Ng, Saie Mogre, Anne R. Diers, Hannah Rockwell, Justice McDaniel, Emily Chen, Fei Gao, Michael Kiebish, Stephane Gesta, Vivek Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan. Coenzyme Q10 (BPM31510-IV in clinical trials) increases mitochondrial Q-pool and modulates electron transport chain function to elicit cell death in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3530.

BPM31510 is a metabolic modulating agent composed of a parenteral nanodispersion of ubidecarenone which is currently in clinical studies for glioblastoma. Glioblastoma is a highly metabolic and aggressive malignancy with limited treatment options and dismal median survival. Temozolomide (TMZ) as a first line treatment option, however, 90% of recurrent gliomas acquire TMZ chemoresistance. Recently, acquisition to TMZ resistance has been correlated to alterations in mitochondrial metabolism. Thus, in the present study we sought to investigate whether BPM31510 could elicit anti-cancer activity in TMZ naïve and TMZ-chemoresistant glioma models. In vitro, in a 2D model BPM31510 treatment demonstrated anti-cancer activity in a panel of glioma cell lines (rat C6 and human U251-MG and U87-MG), and this effect was translatable in spheroidal 3D cultures. Importantly, in an aggressive rat C6 orthotopic glioma model, treatment with BPM31510 (50mg/kg/day, b.i.d) starting between 4 and 8 days post-implantation resulted in a 32% cure rate compared to 0% in controls (P < 0.001, Fisher's exact test), demonstrating an improved survival (P < 0.01, log rank survival), despite producing a minimal change in median survival (13 vs. 12 days). A marked increase in caspase3 staining was observed in tumors from BPM31510 treated animals compared to controls assessed at a similar time point post-tumor implantation, suggesting a strong apoptotic effect of this agent in vivo. Next, BPM31510 was examined in a cellular model of acquired TMZ resistance (TMZ-R) generated by exposing parental (chemosensitive naïve) U251-MG and U87-MG cells to increasing concentrations of TMZ for 9-12 months. Similar to parental cells, BPM31510 displayed anti-cancer activity in both TMZ-R cell models, as decreased cell viability and an increase in the percentage of apoptotic cells was observed upon BPM31510 treatment. Consistent with prior studies, compared to parental cells, TMZ-R cells demonstrated metabolic rewiring characterized by increases in mitochondrial function parameters and decreased extracellular acidification rate, indicative of glycolytic flux. Regardless of chemosensitivity, BPM31510 decreased mitochondrial substrate oxidation (e.g., succinate, glycerol-3-phosphate) at doses which induce cell death. Concomitantly, increases in the reactive oxygen species production were observed with BPM 31510 treatment in both parental and TMZ-R cell lines. Together, these data define a link between regulation of mitochondrial function and the anti-cancer activity of BPM31510 in both TMZ chemo-sensitive and resistant glioblastoma models, demonstrating a distinct approach in targeting mitochondrial metabolism for the treatment of this clinically intractable disease. Citation Format: Tulin Dadali, Shreya Kulkarni, Ryan Ng, Pallavi Awate, Saie Mogre, Anne R. Diers, Taichang Jang, Milton Merchant, Jiaxin Sun, Stephane Gesta, Khampaseuth Thapa, Seema Nagpal, Lawrence Recht, Niven R. Narain, Rangaprasad Sarangarajan. BPM 31510, a clinical stage metabolic modulator, demonstrates therapeutic efficacy in glioblastoma models of temozolomide chemo-sensitive and resistance by targeting mitochondrial function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 873.

Udgivelsesdato: 2008-Mar Tendon reconstruction using grafts often results in adhesions that limit joint flexion. These adhesions are precipitated by inflammation, fibrosis, and the paucity of tendon differentiation signals during healing. In order to study this problem, we developed a mouse model in which the flexor digitorum longus (FDL) tendon is reconstructed using a live autograft or a freeze-dried allograft, and identified growth and differentiation factor 5 (Gdf5) as a therapeutic target. In this study we have investigated the potential of rAAV-Gdf5 -loaded freeze-dried tendon allografts as "therapeutically endowed" tissue-engineering scaffolds to reduce adhesions. In reporter gene studies we have demonstrated that recombinant adeno-associated virus (rAAV)-loaded tendon allografts mediate efficient transduction of adjacent soft tissues, with expression peaking at 7 days. We have also demonstrated that the rAAV-Gdf5 vector significantly accelerates wound healing in an in vitro fibroblast scratch model and, when loaded onto freeze-dried FDL tendon allografts, improves the metatarsophalangeal (MTP) joint flexion to a significantly greater extent than the rAAV-lacZ controls do. Collectively, our data demonstrate the feasibility and efficacy of therapeutic tendon allograft processing as a novel paradigm in tissue engineering in order to address difficult clinical problems such as tendon adhesions.

BPM31510, a parenteral nanodispersion of ubidecarenone that is in clinical testing for solid tumors, effectuates an anti-cancer effect in highly metabolic cancers by eliciting an anti-Warburg effect. Intraperitoneal (i.p.) administration of BPM31510 reverses paraplegia in a rat CNS leukemia model demonstrating the bioavailability of the drug to the central nervous system. The study describes data demonstrating the therapeutic utility of BPM31510 in glioblastoma multiforme (GBM). BPM31510 decreased cell proliferation rates in patient derived GBM cell lines compared to temozolamide (TMZ), pretreatment with BPM31510 followed by TMZ challenge was associated with significant synergy in reducing cell proliferation compared to monotherapy. In a C6 glioma allograft rat model treatment with BPM31510 alone (n=30/group) (i.p., 50mg/kg, b.i.d) increased overall survival compared to untreated control group. BPM31510 in combination with procarbazine (oral, 60mg/kg; d 8, 21) and vincristine (IV, 1.4mg/kg; d 8, 29) significantly improved overall survival compared to BPM31510 alone or chemotherapy. Furthermore, long term survival was achieved in four of twenty rats with C6 gliomas receiving BPM31510 doses between 10 and 50 mg/kg compared with none treated with either vehicle or irradiation (P < 0.02, Fisher exact test). Interestingly, the long term survival persisted for over two months after all treatment was discontinued; MR imaging confirmed the presence of static masses in these long term survivors. Collectively, the data demonstrate that BPM31510 has a robust effect in a preclinical model of GBM. Intravenous BPM31510 is currently in Phase 1/2 clinical trial for TMZ+BEV refractory GBM patients. Citation Format: Stephane Gesta, Semma Nagpal, Tulin Dadali, Milton Merchant, Taichang Jan, Anne R. Diers, Michael Kiebish, Joaquin Jiminez, Vivek K. Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan, Lawrence Recht. BPM31510, a clinical stage metabolic modulator demonstrates therapeutic efficacy in an in vivo C6 rat glioma model and synergizes with temozolomide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4067. doi:10.1158/1538-7445.AM2017-4067

BPM 31510, a clinical stage nanodispersion of ubidecarenone, demonstrates anti-tumor effects by eliciting an anti-Warburg metabolic switch in cancer. Previous studies in an immune compromised PaCa2 xenograft model has unequivocally demonstrated significant efficacy of BPM 31510 on tumor volume and survival. The fundamental property of BPM 31510 to influence mitochondrial bioenergetics and the recognized interplay between T cell metabolism and maturation prompted investigation into the effects of BPM 31510 on T lymphocyte functions in eliciting anti-cancer effects. In this study BPM 31510 selectively influenced activation and maturation of T cells in murine peripheral blood mononuclear cells (PBMCs). Moreover, in addition to determining changes in the CD3+ population, changes in surface expression of PD-1 and CTLA4 along with the IFN-γ secretion were examined. Murine cancer cell lines exposed to BPM 31510 were associated with variable sensitivity with highly metabolic tumor types being most sensitive. Next, the anti-cancer activity of BPM 31510 in an in vivo immunocompetent syngeneic Pan02 rodent model was investigated. Murine Pan02 pancreatic cancer cells were implanted subcutaneously into C57BL/6 mice. Tumors with mean volume of 80 mm3 were treated twice a day with vehicle control or BPM 31510 at 25, 50, 100 mg/kg, administered intraperitoneal. Tumor volumes were measured every 4 days. At day 21 post treatment, tumors were harvested and analyzed for the level of infiltrating immune cells by immunofluorescent staining with CD8+ for T cells and F4/80 for tumor macrophages. These results demonstrate a dose-dependent reduction in tumor volume following 21 days of BPM 31510 treatment. In summary, BPM 31510 exerts potent anti-tumor effects through its dual function of modulating tumor cell metabolism and potentially influencing immune check-point to improve overall survival outcomes. Citation Format: Shiva Kazerounian, Aishwarya Sarma, Nidhi Gaur, Maria D. Nastke, Tulin Dadali, Anne R. Diers, Stephane Gesta, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. BPM 31510, a clinical stage candidate demonstrates potent anti-tumor effect in an immune-competent syngeneic pancreatic cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5576. doi:10.1158/1538-7445.AM2017-5576

Dysregulated mitochondria play a multifaceted role in tumorigenesis through regulation of energy production, biomass, redox state, and engagement of cell death pathways. Perturbations in mitochondrial fluxes (i.e inhibition of electron chain complexes activity, impaired electron flow) have substantial effects on cell viability, suggesting that targeting mitochondrial function could be effective for therapeutic response in cancer. BPM31510, containing oxidized coenzyme Q10 elicits an anti-Warburg effect is currently in phase II clinical trials for solid tumors. Previously, we have demonstrated the anti-cancer properties of BPM31510 in breast and pancreatic xenograft models. Here, we examined the mechanism of action of BPM31510 in vitro. Using a multi-cancer cell panel, BPM31510 was shown to be consistently and selectively cytotoxic to cancer cells, compared to normal and non-tumorigenic controls, and sensitivity did not correlate to cell doubling time or mutational status. Treatment with BPM 31510 (EC50) in breast and pancreatic cancer cells resulted in a time- and dose-dependent decrease in mitochondrial membrane potential which preceded an increase in early and late apoptosis cells, suggesting BPM31510 initiates a mitochondrial mediated cell death pathway. Using a fluorescently labeled CoQ10 we were able to trace the subcellular location of the CoQ10, which predominantly accumulates in mitochondria and lipid droplets in a time dependent manner. Additionally, the mitochondrial enrichment of CoQ10 is accompanied by morphological changes that varied amongst the different cancer cell types. As CoQ10 is a redox molecule required for electron transfer activity between complexes, we hypothesized that disruption of Q-pool homeostasis would alter complex activity. To investigate this, Complex driven respiration was measured in cells treated with BPM31510 and compared to untreated. Alterations in mitochondrial respiration characterized by a dose-dependent decrease in succinate (Complex II) and glycerol-3-phosphate (Complex III)-fueled respiration were observed in cells treated with BPM31510, while no changes were seen in pyruvate driven respiration (Complex I), suggesting that BPM31510 specifically impairs respiration responses that are more dependent on Q-pool functionality. As impairment of the electron transport chain increases intracellular oxidative stress, we next investigated if BPM 31510 treatment increases ROS levels. After 24h treatment, BPM31510 significantly increased ROS levels in treated cancer cells compared to untreated. Furthermore, BPM31510 induced death could be in part prevented by co-treatment with antioxidants. Together, these data demonstrates BPM31510 has anti-cancer activity in multiple cancer cell types and define a unique and novel functional link between mitochondrial Q-pool disruption and the mechanism of action of BPM31510. Citation Format: Tulin Dadali, Katerina Krumova, Anne R. Diers, Pallavi Awate, Ryan Ng, Arleide Lee, Stephane Gesta, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. BPM31510 modulates mitochondrial complex activity to influence oxidative stress in effectuating cell death in multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1497. doi:10.1158/1538-7445.AM2017-1497

e13509 Background: Glioblastoma (GB) is characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone containing lipid nanodispersion effectuates a switch in cancer energy sourcing from glycolysis towards mitochondrial OXPHOS, i.e. reverses Warburg effect, providing rationale for its potential utility in treatment of GB. The current study investigated utility of BPM31510 alone and in combination with temozolomide. Methods: In vitro (U251-MG human GB cell line) and in vivo (C6 glioma rat model) preclinical models of GB were used to assess the anti-cancer activity of BPM 31510 alone (100 mg/kg/d) and combination with TMZ/bevacizumab (BEV). In addition, an in vitro model of acquired TMZ chemo-resistance was established by progressive adaptation of parental U251-MG cells to increasing doses of TMZ. Parental and resistant subclones (TMZ-R) were used to define activity of BPM31510 in the TMZ-refractory setting. Results: In vitro results demonstrated that BPM 31510 has anti-cancer activity in both parental and TMZ-R U251-MG cells with EC50 values of ~400 µM and 800 µM, respectively. Importantly, BPM 31510 treatment also resensitized TMZ-R cell lines to TMZ. In vivo, BPM 31510 treatment was associated with increasing duration of survival; one fifth of the rats treated achieved survival greater than 15 days post implantation, a response not observed in the control or irradiation arms of the study. Assessment of the combination of BPM 31510 with TMZ or BEV in the in vivoC6 glioma rat model is ongoing. A phase I open-label, non-randomized clinical trial to evaluate the safety and tolerability of BPM31510 in patients with recurrent BEV-refractory GB, as well as the changes in GB metabolism by SUV-PET imaging in response to treatment is under investigation. Conclusions: Preclinical data demonstrate that BPM 31510 has potential anti-cancer activity alone and in combination with standard therapy regimens and alleviates TMZ chemo-resistance in preclinical models of GB. These results provide support of a Phase 1 clinical study of BPM31510 in GB; this study is actively enrolling.

By means of a phenomenon termed “the Warburg effect,” tumor cells shift their energy production by mitochondrial oxidative phosphorylation to aerobic glycolysis, resulting in the upregulation of glucose consumption and increased cellular oxidative and nitrosative stress. To compensate for such toxic levels of ROS/RNS, cancer cells rely heavily on their antioxidant defense mechanisms, which are largely controlled by the NAD(P)/NAD(P)H redox partners. We found that the modulation of NAD metabolism in vivo, specifically via the deletion of the NAD glycohydrolase CD38, resulted in increased production of intrinsic ROS and increased DNA damage following exposure to chemotherapeutics. Furthermore, in vitro experiments showed that CD38 knockdown in CD38-expressing tumor cells prevented the generation of stable transfectants, highlighting a role for CD38 in tumor cell survival. In light of these findings, we hypothesized that pharmacological inhibition of CD38 may be an effective therapy for the treatment of hematological cancers, in particular those which uniformly overexpress CD38, such as MM and chronic lymphocytic leukemia. Indeed, treatment of human MM cell lines LP-1 and KMS-12-PE with CD38 antagonists sensitized the cells to standard ROS-inducing chemotherapeutics. We conducted a high-throughput screening (HTS) campaign of over two hundred thousand unique and non-proprietary lead-like compounds using an optimized and miniaturized HTS based on a luminescent NAD quantitation platform. Five hundred active hits were analyzed for toxicity using a cell-based HTS assay purposely designed with CD38-negative HEK293 cells to avoid elimination of desirable compounds toxic to CD38-positive cells. Hits with non-specific properties, such as PAINS (Pan Assay Interference Compounds), were removed by computational filtering, and the remaining compounds were tested for inhibition of human CD38 activity in cells. The last phase of the compound progression pathway involved testing for non-selective inhibition of other NAD-consuming enzymes, namely Poly(ADP-ribose) polymerase-1, and Sirtuin-1, which led to the identification of two distinct chemical series that exhibit >10-fold selectivity for human CD38. Hit-to-lead chemistry is currently underway to synthesize key analogs by rational drug design. In summary, our data suggests that CD38 is an antioxidant protein selectively used to maintain a cellular redox balance, and proposes that targeting the enzymatic activity of CD38 may be a novel therapeutic strategy for chemosensitizing hematological cancers. Our HTS campaign efforts are paving the way for the discovery and development of potent and selective small-molecule inhibitors of CD38. Citation Format: Davide Botta, Tulin Dadali, Betty J. Mousseau, Fen Zhou, Michael D. Schultz, Esther Zumaquero, Anna Manouvakhova, Melinda I. Sosa, Sara N. McKellip, LaKeisha Woods, Nichole A. Tower, Larry J. Ross, Lynn Rasmussen, E. Lucille White, Indira Padmalayam, Wei Zhang, Maaike Everts, Corinne E. Augelli-Szafran, James R. Bostwick, Mark J. Suto, Frances E. Lund. High-throughput screening efforts for the identification of selective and potent inhibitors of CD38 for the treatment of hematological cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-055.

De-regulated lipid homeostasis is a key feature of the altered metabolic phenotype observed in cancer, particularly in the adipose-rich microenvironment of breast tumors. Mitochondria serve as a central hub for lipid metabolism through mitochondrial β-oxidation pathways and biosynthesis through production of citric acid cycle-derived citrate and the activity of ATP citrate lyase, the rate-limiting enzyme in lipid biosynthesis. We have previously demonstrated BPM 31510 ability to effectuate Warburg switch from glycolysis to mitochondrial oxidative phosphorylation resulting in activation of apoptosis in multiple cancers including triple negative breast cancer. The present investigated the role of BPM 31510 in influencing lipid metabolism in cancer cells to arbitrate its anti-cancer effect. Cell viability was assessed in MDA-MB231 and SkBr-3 breast cancer cells exposed to BPM 31510 alone or in combination with fatty metabolism inhibitors including C75, etomoxir, and trimetazidine, inhibitors of fatty acid synthase (FASN), carnitine palmitoyltransferase 1 (CPT-1), and β-oxidation, respectively, as well as a more pleiotropic fatty acid metabolism modulator, metformin. Breast cancer cells were more sensitive to BPM 31510 when treated in combination with C75, etomoxir, and trimetazidine as indicated by a left-shift in the BPM 31510 dose-response curve in both MDA-MB231 and SkBr-3 cells. In contrast, combined treatment with metformin did not alter cytotoxic responses to BPM 31510, indicating specificity for responses in fatty acid metabolism pathway modulation. Interestingly, BPM31510 treatment was associated with a dose- and time-dependent increase in mRNA expression of fatty acid metabolism gene products (FASN, CPT1, ACSL1) and accumulation of the triglyceride backbone, glycerol, in MDA-MB-231 cells. Structural lipidomic analysis used to assess the metabolic fate of BPM 31510 liposomal formulation components demonstrated that these were readily incorporated into prevalent diacyl-glyerol (DAG) and triacyl-glycerol (TAG) species along with de novo fatty acid species such as palmitate. Together, these results demonstrate that BPM 31510 alters endogenous and exogenous lipid homeostasis in breast cancer cells and rationale for potential combination with fatty acid metabolism inhibitors for anti-cancer therapy. The results expands on BPM 31510 anti-cancer mechanism, suggesting a central role in arbitrating the convergence of glycolysis, glucose and fatty acid oxidation pathways within the cancer cell metabolism network. Citation Format: Bianca Jambhekar, Tulin Dadali, Anne R. Diers, Fei Gao, Hannah Rockwell, Emily Chen, Stephane Gesta, Vivek K. Vishnudas, Michael A. Kiebish, Niven R. Narain, Rangaprasad Sarangarajan. The anti-Warburg agent BPM 31510 arbitrates fatty acid metabolism in eliciting an anticancer response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1014.

Although only 15-20% of total breast cancer diagnoses are of the triple-negative breast cancer (TNBC) subtype, they account for a significant portion of the mortality rate due to their more aggressive phenotype and a high risk of reoccurrence. Metabolic rewiring supports breast cancer progression and metastasis, particularly in ER-negative and triple-negative (TNBC) breast tumors. Thus, we examined the effects of BPM 31510, a metabolic-modulating agent in clinical trials for solid tumors, in in vitro and in vivo ER-negative and TNBC models. BPM 31510 EC50/EC>90 values were determined for a panel of the breast cancer cell lines and compared to non-tumorigenic MCF12A cells in vitro, and the MDA-MB231 and SkBr-3, TNBC and ER-negative models respectively, were found to be the most sensitive to BPM 31510. Treatment with BPM 31510 (EC50 and EC>90 doses) resulted in a time- and dose-dependent decrease the viable cell population (PI- and Annexin V-negative) and a concomitant increase in cells in early and late apoptosis (PI-negative and PI-positive Annexin V-positive cells, respectively), suggesting that BPM 31510 activates regulated cell death pathways. Consistent with the in vitro data, MDA-MB231 tumor-bearing mice had smaller tumors after 30 days of treatment with BPM 31510 and increased cleaved caspase 3 staining in resected tumors. In vitro, BPM 31510-dependent breast cancer cell death was preceded by mitochondrial membrane potential depolarization (TMRE flow cytometry) and alterations in mitochondrial respiration characterized by a consistent, dose-dependent decrease in succinate (Complex II)-fueled respiration with more varied responses to BPM 31510 in cells provided the Complex I substrates (pyruvate or palmitoyl carnitine). To investigate the role of Complex II in BPM 31510-mediated cell death, pharmacological inhibitors of the dicarboxylate site (malonate) and Qp site (atpenin A5) of Complex II were used in combination with BPM 31510 to assess the resultant effects on cell death in MDA-MB231 cells. Co-treatment with malonate significantly attenuated BPM 31510-mediated cell death while atpenin A5 did not affect BPM 31510-induced cell death, indicating succinate oxidation at the dicarboxylate site of Complex II is required, in part, for induction of cell death by BPM 31510. Together, these data demonstrate BPM 31510 has a potent anti-cancer activity in preclinical breast cancer models and define a functional link between Complex II activity and the mechanism of action for BPM 31510. Citation Format: Tulin Dadali, Anne R. Diers, Arleide Lee, Ezer Benaim, Joaquin J. Jimenez, Stephane Gesta, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. BPM 31510-induced alteration in Complex II activity is functionally linked to cell death activation pathway in a preclinical model of triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 208.

Pancreatic adenocarcinoma (PanCa) is associated with poor prognosis and overall survival. Current first-line therapeutics are cytotoxic agents targeting DNA based mechanistic end-points for efficacy, their use limited by dose associated toxicity. There is a critical need for therapeutics with novel mechanisms amenable to combination with current standard-of-care chemotherapy to improve outcomes. BPM 31510 is a drug that targets cellular metabolism networks, effectuating an anti-Warburg effect in cancer. The documented high metabolic phenotype observed in PanCa provided rationale for investigation of BPM 31510 alone and in combination with gemcitabine in in vitro and in vivo PanCa models. Based on BPM 31510 EC50/EC>90 values for MIA-PaCa-2 and Panc-1 PanCa cell lines in vitro, the PanCa cells were significantly more sensitive to BPM 31510 compared to fibroblasts. BPM 31510 treatment in a time- and dose-dependent manner decreased the PI- and Annexin V-negative (viable) population and a concomitant increase in the percentage of Annexin V-positive cells, with PI indicative of early and late apoptosis. The anti-cancer activity of BPM 31510 was assessed in vivo using MIA-PaCa-2 tumor-bearing immune-compromised mice. Treatment with increasing doses of BPM 31510 (0.5-50 mg/kg IP, 3X/week) significantly improved survival outcomes, with the highest dose extending median survival by more than 36 days compared to saline control. Moreover, combined treatment with BPM 31510 and gemcitabine (150 mg/kg IV, 1X/week, given on cycles, 3 weeks on 1 week) resulted in further extension of median survival over either treatment alone. The mechanistic underpinnings for the enhanced efficacy of combination treatment were explored in vitro. In MIA-PaCa-2 cells, co-treatment with BPM 31510 and gemcitabine increased indices of regulated cell death higher than observed for either treatment alone. In contrast, although treatment with either BPM 31510 or gemcitabine alone increased caspase-3 activity, co-treatment did not enhance caspase-3 activation, suggesting that BPM 31510 augments gemcitabine cytotoxicity through independent mechanisms. In fact, BPM31510, and not gemcitabine, increased the mitochondrial uncoupling efficient ratio and Stateapparent in MIA-PaCa-2 cells. Nonetheless, co-treatment with BPM 31510 and gemcitabine synergistically decreased the mitochondrial membrane potential (ΔΨm) in cells prior to cell death. Taken together, these data indicate that BPM 31510-driven bioenergetic alterations are separate from the effects of gemcitabine; however, their effects converge at the mitochondrion to dissipate ΔΨm and activate regulated cell death. The data suggests that combination of BPM 31510 with gemcitabine in pancreatic cancer will effectuate an efficacy response via independent mechanisms with improvement in therapeutic outcome. Citation Format: Tulin Dadali, Anne R. Diers, Rakib Ouro-Djobo, Justin Bourdelais, Ezer Benaim, Bianca Jambhekar, Tony E. Walshe, Vivek K. Vishnudas, Joaquin J. Jimenez, Rangaprasad Sarangarajan, Niven R. Narain. BPM 31510 synergizes gemcitabine efficacy in pancreatic adenocarcinoma via mechanism independent of its anti-Warburg influence on metabolism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 212.

T regulatory cells (Tregs) are a subset of FoxP3+ lymphocytes that maintain immune homeostasis through immunosuppressive signaling. In many helminth infections, one mechanism of immune evasion involves the influx and maintenance of Tregs. Multiple mechanisms can control Treg homeostasis including a Nicotinamide adenine dinucleotide (NAD) dependent apoptotic pathway. In most organisms, the two pathways of NAD synthesis include de novo synthesis from amino acid precursors, and the salvage pathway in which nicotinamide-containing precursors are recycled into NAD. A comparative genome analysis of S. mansoni, the parasite that causes Schistosomiasis, enabled the assembly of a putative NAD biosynthetic pathway. Only orthologues of NAD salvage-specific genes were identified and expression was confirmed by PCR. This suggests that S. mansoni decreases host NAD levels in a salvage-specific manner and rescues Tregs from NAD-dependent cell death. As such, we hypothesized that inhibition of NAD biosynthesis through the salvage pathway would result in impaired NAD uptake by S. mansoni and restoration of NAD-mediated cell death of Tregs. Indeed, co-culture with S. mansoni prevented NAD-induced toxicity and death of Tregs. Blockade of the NAD salvage pathway via the inhibition of Schistosoma mansoni NAD catabolizing enzyme (SmNACE) restored NAD-mediated cell death of Tregs. Furthermore, SmNACE inhibition decreased intracellular NAD levels and reduced metabolism and viability of the parasite. Collectively, our data suggest that inhibition of NAD biosynthesis blocks immune evasion and metabolism of S. mansoni, and that targeting the NAD salvage pathway is a promising therapeutic approach for the treatment of Schistosomiasis.

The use of processed structural allografts for treatment of massive segmental defects in long bones can be complicated by poor incorporation and remodeling of the devitalized graft, foreign-body reaction and micro-damage accumulation which often leads to catastrophic graft failure [1]. It is therefore useful to develop a bioengineered, biodegradable scaffold that is able to stimulate healing of the defect region. The use of bioengineered scaffolds has been limited due to their poor mechanical strength that does not permit withstanding large in vivo loads and due to their poor osteoinductive properties. We therefore investigated the use of rigid polylactic acid/beta-tricalcium phosphate (PLA/βTCP) composites used in conjunction with osteoinductive factors such as growth hormones (parathyroid hormone (PTH)) and growth factors (bone morphogenic protein-2 (BMP-2) & vascular endothelial growth factor (VEGF)) to stimulate bone formation and vessel ingrowth in the segmental defect region. We examined the physical characteristics of the scaffolds, and evaluated their osteoinductive potential in a clinically-relevant mouse model of a femoral segmental defect with or without PTH treatment. Finally, we used an ectopic bone formation model to assess the efficacy of the scaffold in site-specific delivery of bone anabolic factors.Copyright © 2008 by ASME

Reconstruction of flexor tendons often results in adhesions that compromise joint flexion. Little is known about the factors involved in the formation of flexor tendon graft adhesions. In this study, we developed and characterized a novel mouse model of flexor digitorum longus (FDL) tendon reconstruction with live autografts or reconstituted freeze-dried allografts. Grafted tendons were evaluated at multiple time points up to 84 days post-reconstruction. To assess the flexion range of the metatarsophalangeal joint, we developed a quantitative outcome measure proportional to the resistance to tendon gliding due to adhesions, which we termed the Gliding Coefficient. At 14 days post-grafting, the Gliding Coefficient was 29- and 26-fold greater than normal FDL tendon for both autografts and allografts, respectively (p < 0.001), and subsequently doubled for 28-day autografts. Interestingly, there were no significant differences in maximum tensile force or stiffness between live autograft and freeze-dried allograft repairs over time. Histologically, autograft healing was characterized by extensive remodeling and exuberant scarring around both the ends and the body of the graft, whereas allograft scarring was abundant only near the graft-host junctions. Gene expression of GDF-5 and VEGF were significantly increased in 28-day autografts compared to allografts and to normal tendons. These results suggest that the biomechanical advantages for tendon reconstruction using live autografts over devitalized allografts are minimal. This mouse model can be useful in elucidating the molecular mechanisms in tendon repair and can aid in preliminary screening of molecular treatments of flexor tendon adhesions.

Despite global advances in cancer detection and treatment in some indications, the early diagnosis and overall survival rate for pancreatic cancer (PanCa) remains dismal. Thus, there is a critical need for novel therapeutics that may combine well with standard-of-care therapy or work through novel mechanisms. Given that most pancreatic tumors exhibit a highly metabolic phenotype, we examined the effects of BPM 31510 employing in vitro and in vivo PanCa models. BPM 31510 is a metabolic-modulating agent that reverses the Warburg effect and is currently in clinical development for solid tumors alone and in combination with chemotherapy. Determination of BPM 31510 IC50 values in vitro demonstrated the PanCa cell lines MIA PaCa-2 and Panc-1 cells were significantly more sensitive to BPM 31510 (IC50 = 137 and 455 μM, respectively) compared to primary fibroblasts (IC50 = 1537 μM). IC50 and IC90 doses of BPM 31510 also decreased the viable cell population while concomitantly increasing Annexin V- and PI-positive populations in both PanCa cell types, indicating BPM 31510 induces programmed cell death. Furthermore, in combination with gemcitabine (0.1-5 μM), BPM 31510 (100 μM) decreased cell viability by more than 75% compared to either treatment alone. In vivo, treatment of MIA PaCa-2 tumor-bearing mice with increasing doses of BPM 31510 (0.5-50 mg/kg IP, 3X/week) significantly improved median survival in a dose-dependent manner, with the highest dose extending median survival by more than 36 days compared to saline control. Moreover, while median survival of MIA PaCa-2 tumor-bearing mice treated with BPM 31510 (50 mg/kg IP, 1X/day) or gemcitabine (150 mg/kg IV, 1X/week, given on cycles, 3 weeks on 1 week) monotherapy was 77 and 63 days, respectively, combination treatment resulted in median survival improvement to 113.5 days. Examination of alternative dosing regimens revealed that more frequent dosing of BPM 31510 (2X or 3X/day) alone and in combination with gemcitabine further extended median survival in this model. The preliminary mechanistic insight into additive efficacy of combination treatment was explored in vitro. BPM 31510 treatment alone significantly altered multiple aspects of mitochondrial function in MIA PaCa-2 cells, indicating that BPM 31510-driven bioenergetic alterations are separate from the effects of gemcitabine. Hence, these data demonstrate that BPM 31510 has a potent anti-cancer activity alone and in combination with standard-of-care chemotherapy in preclinical PanCa models. Citation Format: Tulin Dadali, Anne R. Diers, Arleide Lee, Rakibou Ouro-Djobo, Justin Bourdelais, Ezer Benaim, Bianca Jambhekar, Tony E. Walshe, Joaquin J. Jimenez, Vivek K. Vishnudas, Rangaprasad Sarangarajan, Niven R. Narain. BPM 31510 enhances efficacy of gemcitabine through orthogonal mechanisms in a preclinical model of pancreatic adenocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C117.

The cellular redox state, which is controlled by the NAD/NADH and NADP/NADPH redox partners, is critical for numerous cellular activities including energy metabolism, signaling and transcription. Hematopoietic tumors have higher levels of intrinsic reactive oxygen species (ROS) due to increased NAD biosynthesis and metabolism required to further stimulate tumorigenesis. To compensate for such toxic levels of ROS, cancer cells rely heavily on their antioxidant defense mechanisms to prevent ROS-induced death/senescence and to promote neoplastic cell behavior. It has been postulated that pairing drugs that block the tumor antioxidant pathways with ROS-inducing chemotherapeutics may kill tumors more effectively. We hypothesized that the modulation of NAD metabolism dramatically alters the cellular redox state, and that drugs affecting NAD metabolism may be effective anti-cancer therapeutics. Using an in vivo model of Streptozotocin (STZ)-induced oxidative stress, we show that the NAD glycohydrolase CD38, which is expressed by many B-cell malignancies, acts as an antioxidant by lowering intrinsic ROS levels and by protecting cells from extrinsic ROS, DNA alkylating chemotherapeutics and ROS-induced senescence. In addition, we show that the overexpression of human CD38 increases the viability of murine Ba/F3 pro-B cells cultured in the absence of the survival factor IL-3. To examine the role of CD38 in tumor cell growth and survival, we reduced CD38 expression in human multiple myeloma KMS-12-PE cells by RNA interference (RNAi) targeting three separate regions of the CD38 coding sequence. The knockdown of CD38 expression resulted in a significant decrease in the number of stable transformants generated, suggesting that CD38 plays a key role in tumor cell survival. Lastly, we show that CD38 antagonists synergize with the chemotherapeutic agent Melphalan to block tumor cell survival in vitro. In summary, this work suggests that CD38 is an antioxidant protein selectively used to maintain a cellular redox balance, and proposes that targeting the enzymatic activity of CD38 may be a novel therapeutic strategy for chemosensitizing B-cell malignancies. We are currently conducting a high-throughput screening (HTS) campaign of over 200 thousand small-molecule compounds to identify inhibitors of CD38 that can be used in combination with standard ROS-inducing chemotherapies to treat CD38+ B-cell malignancies, such as multiple myeloma and chronic lymphocytic leukemia. Citation Format: Davide Botta, Tulin Dadali, Betty Mousseau, Anna Manouvakhova, Melinda I. Sosa, Sara N. MKellip, LaKeisha Woods, Nichole A. Tower, Larry J. Ross, Lynn Rasmussen, E Lucile White, James R. Bostwick, Frances E. Lund. Modulating the cellular redox state by targeting the NAD glycohydrolase CD38: A novel therapeutic approach for chemosensitizing B-cell malignancies. [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 1242. doi:10.1158/1538-7445.AM2015-1242