Burkhart C.,Buffalo Biolabs, Llc |
Fleyshman D.,Roswell Park Cancer Institute |
Kohrn R.,Buffalo Biolabs, Llc |
Commane M.,Roswell Park Cancer Institute |
And 6 more authors.
Oncotarget | Year: 2014
Pancreatic ductal adenocarcinoma (PDA) continues to be one of the deadliest cancers due to the absence of effective treatment. Curaxins are a class of small molecules with anti-cancer activity demonstrated in different models of cancer in mice. The lead curaxin compound, CBL0137, recently entered Phase I clinical trials. Curaxins modulate several important signaling pathways involved in the pathogenesis of PDA through inhibition of chromatin remodeling complex FACT. FACT is overexpressed in multiple types of tumor, with one of the highest rate of overexpression in PDA (59%). In this study, the efficacy of CBL0137 alone or in combination with current standard of care, gemcitabine, was tested against different models of PDA in vitro and in mouse models. It was found that CBL0137 alone is a potent inducer of apoptosis in pancreatic cancer cell lines and is toxic not only for proliferating bulk tumor cells, but also for pancreatic cancer stem cells. In mice, CBL0137 was effective against several PDA models, including orthotopic gemcitabine resistant PANC-1 model and patient derived xenografts, in which CBL0137 anti-tumor effect correlated with overexpression of FACT. Moreover, we observed synergy of CBL0137 with gemcitabine which may be explained by the ability of CBL0137 to inhibit several transcriptional programs induced by gemcitabine, including NF-kappaB response and expression of ribonucleotide reductase, one of the targets of gemcitabine in cells. This data suggest testing of CBL0137 efficacy in Phase II trial in PDA patients alone and in combination with gemcitabine.
PubMed | Buffalo Biolabs, Llc, Cellecta, Inc., Roswell Park Cancer Institute and Sanford Burnham Institute for Medical Research
Type: | Journal: Cell death & disease | Year: 2016
shRNA-mediated gene-silencing technology paired with cell-based functional readouts reveals potential targets directly, providing an opportunity to identify drugs against the target without knowing the precise role of the target in the pathophysiological processes of interest. By screening a lentiviral shRNA library targeting for major components of human signaling pathways and known drug targets, we identified and validated both canonical as well as 52 novel mediators of FAS and TNF ligand-induced apoptosis. Presence of potential therapeutic targets among these mediators was confirmed by demonstration of in vivo activity of siRNAs against four identified target candidates that protected mice from acute liver failure (ALF), a life-threatening disease with known involvement of death receptor (DR)-mediated apoptosis. Network-based modeling was used to predict small-molecule inhibitors for several candidate apoptosis mediators, including somatostatin receptor 5 (SSTR5) and a regulatory subunit of PP2A phosphatase, PPP2R5A. Remarkably, pharmacological inhibition of either SSTR5 or PPP2R5A reduced apoptosis induced by either FASL or TNF in cultured cells and dramatically improved survival in several mouse models of ALF. These results demonstrate the utility of loss-of-function genetic screens and network-based drug-repositioning methods for expedited identification of targeted drug candidates and revealed pharmacological agents potentially suitable for treatment of DR-mediated pathologies.
Kojouharov B.M.,Roswell Park Cancer Institute |
Brackett C.M.,Roswell Park Cancer Institute |
Veith J.M.,Roswell Park Cancer Institute |
Johnson C.P.,Roswell Park Cancer Institute |
And 8 more authors.
Oncotarget | Year: 2014
Myelosuppression and gastrointestinal damage are common side effects of cancer treatment limiting efficacy of DNA-damaging chemotherapeutic drugs. The Toll-like receptor 5 (TLR5) agonist Entolimod has demonstrated efficacy in mitigating damage to hematopoietic and gastrointestinal tissues caused by radiation. Here, using 5-Fluorouracil (5-FU) treated mice as a model of chemotherapy-induced side effects, we demonstrated significant reduction in the severity of 5-FU-induced morbidity and increased survival accompanied by the improved integrity of intestinal tissue and stimulated the restoration of hematopoiesis. Entolimod-stimulated IL-6 production was essential for Entolimod's ability to rescue mice from death caused by doses of 5-FU associated with hematopoietic failure. In contrast, IL-6 induction was not necessary for protection and restoration of drug-damaged gastrointestinal tissue by Entolimod. In a syngeneic mouse CT26 colon adenocarcinoma model, Entolimod reduced the systemic toxicity of 5-FU, but did not reduce its antitumor efficacy indicating that the protective effect of Entolimod was selective for normal, non-tumor, tissues. These results suggest that Entolimod has clinical potential to broaden the therapeutic window of genotoxic anticancer drugs by reducing their associated hematopoietic and gastrointestinal toxicities.
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 100.00K | Year: 2012
DESCRIPTION (provided by applicant): Rhabdomyosarcoma (RMS) is a childhood malignant tumor and is thought to arise due to the arrest of skeletal muscle differentiation (myogenesis) program. It accounts for 3.5% of all malignancies in children. Despite multimodality therapeutic treatment approaches, the outlook for patients with metastatic subtype, alveolar rhabdomyosarcoma (ARMS), remains unchanged. Moreover, conventional toxic chemotherapeutic strategies fail to succeed for the treatment of metastatic rhabdomyosarcoma; therefore, urgent need of novel approaches for the development of new pharmaceuticals to treat this dreadful disease. Because rhabdomyosarcoma cells are defective to complete myogenic terminal differentiation program, restoration of this abortive differentiation program in these cels would be a novel promising anti-RMS chemotherapeutic approach. The ultimate goal of this proposal is to develop novel approach-based new pharmaceuticals capable of restoring the differentiation block in rhabdomyosarcoma cells for the treatment of metastatic rhabdomyosarcoma. While studying the anti-muscle differentiation mechanisms in alveolar rhabdomyosarcoma (ARMS) cells, we found increased level of epigenetic modifier histone H3 lysine-9 methyltransferase Suv39Hprotein (referred herein KMT1A as per new nomenclature) when these cells were grown in differentiation conditions. Investigation into the mechanism of induced KMT1A expression in the arrest of ARMS cell differentiation led us a recent publication (CancerRes. (2011) 71(11): p. 3921-31). In this study, we have demonstrated that KMT1A depletion by shRNA restores growth arrest and terminal myogenic gene expression mediated by MyoD, which acts as a key myogenic transcriptional regulator of myogenic program anduniversally expresses in RMS cells. Moreover, KMT1A depleted ARMS cells fail to develop tumor in vivo. Thus, we are considering KMT1A as a prospective target for developing pharmaceuticals for restoration of MyoD mediated terminal differentiation as an unconventional novel chemotherapeutic strategy for the treatment of metastatic rhabdomyosarcoma disease. The current proposal is focused on exploiting this opportunity as a first step towards developing anti- KMT1A pharmaceuticals for the treatment of ARMS.We will use functional screening of small molecule chemical libraries to identify KMT1A inhibitors capable of inducing MyoD-mediated terminal differentiation in ARMS cells. Specifically, we plan to: 1) Small molecule chemical library screening for inhibitors of KMT1A that re-activate MyoD mediated transcription. 2) Characterization of hits for their ability to suppress KMT1A mediated inhibition of MyoD-induced muscle differentiation in metastatic RMS (ARMS) cells. Completion of this proposal should identify KMT1A inhibitors capable of reprogramming MyoD mediated terminal differentiation in ARMS cells and provide a solid platform for subsequent development of KMT1A antagonist pharmaceuticals for clinical applications to treat metastatic rhabdomyosarcoma and other diseases associated with KMT1A deregulation PUBLIC HEALTH RELEVANCE: Metastatic rhabdomyosarcoma (alveolar subtype, ARMS) is incurable using current treatment strategies. Targeting the histone H3 lysine-9 methyltransferase Suv39H, which appears to block MyoD-mediated terminal myogenic program in ARMS cells, represents a novel treatment strategy for the reactivation of MyoD, a key myogenic differentiation factor, in ARMS. This approach should provide a more efficacious and less toxic alternative to current treatment strategies and, thus, has major implications for the therapeutic management of all children with this aggressive disease.
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 300.00K | Year: 2012
DESCRIPTION (provided by applicant): Mortality from pancreatic ductal adenocarcinoma (PDA) is close to 100% due to the absence of effective treatment approaches. This proposal is focused on determining the therapeutic potential of a new class of candidateanti-cancer agents named Curaxins (CXs) for treatment of PDA. The rationale for this is based on our discovery that CXs inhibit the activity of the Facilitate Chromatin Transcription (FACT) complex, which is overexpressed in ~60% of PDA. Inhibition of FACT by CXs leads to suppression of several stress response signaling pathways, including NF-kB and heat shock factor 1 (HSF1). This mechanism of action can be predicted to impact PDA since one of the most significant factors predisposing to PDA is chronic inflammation with constitutive activity of NF-kB. Heat shock response, mediated by HSF1, is frequently overactive in PDA cells. Our preliminary tests showed that CXs are toxic to PDA cells and tumors, including those resistant to the current standard of care, gemcitabine (GC). To meet our overall goal of advancing CXs towards clinical use for treatment of PDA, we propose the following Specific Aims: 1. To select the optimal CX compound ( CX-X ) for anti-PDA clinical development. Four CXs were selected following structure activity relationship (SAR) studies. These synthetic, structurally-related small molecules demonstrated the best in vitro activity (effects on p53 and NF-:B, toxicity to tumor cells), in vivo activity (low toxicity in mice, yet effective against tumors) and pharmacological properties. The four CXs will be tested for in vitro toxicity against a panel of established PDA cell lines as well as primary cells isolated from surgical samples of PDA separated into pancreatic cancer stem cells (PCSC) and bulk PDA cells based on expression of PCSC markers (CD24, CD44 and ESA). The CX concentration killing the majority of cells (LC90) will be determined for each cell sample. In parallel, we will measure CX accumulation in the pancreas of treated mice. TheCX molecule with the highest ratio of intra-pancreas concentration to LC90 in PDA cells ( CX- X ) will be selected for use in Aims 2 and 3. 2. To determine the efficacy of CX-X in mouse models of Gemcitabine-sensitive and -resistant PDA. Gemcitabine(GC) is currently the main agent used in patients with advanced PDA. Although GC is effective in some patients, most demonstrate intrinsic or acquired resistance to the drug. Our preliminary data indicate that CXs inhibit growth of GC-resistant PDA tumorsand also have a synergistic effect with GC against PDA. In this Aim, we will further explore the possibility of using CXs to treat GC-resistant PDA tumors using CX-X alone or in combination with GC against a larger number of patient tumor samples grown in mice. 3. To assess tumor expression of the FACT subunit SSRP1 as a potential marker of sensitivity to CX treatment and to develop a pharmacodynamic assay based on this. SSRP1 is expressed at a high level in many types of tumors (including PDA), but isundetectable in most normal tissues (Preliminary data). In the proposed studies, we will analyze protein and RNA level of both FACT subunits in PDA samples used for the treatment with CX in aim 2. In addition, we will assess the level of total and free soluble SSRP1 (sSSRP1) in tumor samples obtained from aim 2 in vitro and in vivo and to see if the level of total SSRP1 has any correlation with response of tumor to CX treatment (predictive marker) and if the level of sSSRP1 is reduced in response to CX treatment (pharmacodynamic marker). Successful completion of this aim will likely provide valuable markers for use in clinical trials. PUBLIC HEALTH RELEVANCE: This project is devoted to the development of a new type of treatment of one of the mostaggressive types of cancer pancreatic ductal adenocarcinoma (PDA). Treatment options for patients with PDA are currently very limited and prognosis is very poor. We have recently discovered and development new types of anti-cancer agents, named Curaxins (CXs). CXs act through inhibition of Facilitate Chromatin Transcription (FACT) complex, involved in RNA transcription, DNA replication and cell proliferation (mitosis). They also modulate several signaling pathways important for PDA progression. Preliminarydata demonstrated that CXs are toxic for PDA cells in vitro and in vivo and therefore may be proposed as a candidate anti-cancer agent for PDA.
PubMed | Cleveland BioLabs Inc., Buffalo Biolabs, Llc and Roswell Park Cancer Institute
Type: | Journal: Cancer research | Year: 2016
Isolated limb perfusion (ILP) with the chemotherapeutic agent melphalan is an effective treatment option for extremity in-transit melanoma but is toxic and technically challenging to deliver locoregionally. CBL0137 is an experimental clinical drug with broad anticancer activity in animal models, owing to its ability to bind DNA in a nongenotoxic manner and inactivate the FACT chromatin modulator essential for tumor cell viability. Here, we report that CBL0137 delivered by ILP in a murine melanoma model is as efficacious as melphalan, displaying antitumor activity at doses corresponding to only a fraction of the systemic MTD of CBL0137. The ability to bind DNA quickly combined with a favorable safety profile made it possible to substitute CBL0137 in the ILP protocol, using an intra-arterial infusion method, to safely achieve effective tumor suppression. Our findings of a preclinical proof of concept for CBL0137 and its administration via intra-arterial infusion as a superior treatment compared with melphalan ILP allows for locoregional treatment anywhere a catheter can be placed. Cancer Res; 76(22); 1-11. 2016 AACR.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 200.00K | Year: 2012
Head and neck (HandN) cancer is recognized as a significant threat to public health and a substantial economic challenge. The efficacy of radiotherapy widely used to treat HandN cancer is limited by severe adverse effects, such as mucositis. Currently, there are no drugs effectively preventing these complications. This situation constitutes a significant problem and an outstanding business opportunity for the development of new clinical radioprotectors to improve safety and efficiency of HandN cancer radiation therapy. This Phase I application is focused on exploring applicability of Protectan CBLB502 in minimizing radiation damage to healthy tissues in HandN cancer radiation treatment. The results of preliminary studies published by the investigators of this project provided the first evidence of feasibility of the proposed strategy. The Research Plan includes two specific aims that would (i) demonstrate protective effect of CBLB502 for healthy HandN tissues irradiated under close-to-clinical radiation regimen in mice; and (ii) explore the combination of radiation/CBLB502 treatment for improvement of efficacy and safety of radiotherapy in mouse model of HandN cancer. These milestones will provide a starting point for the Phase II program to complete preclinical studies, open an IND and start a clinical trial in patients with HandN cancers.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.50M | Year: 2011
Aberrant functioning of proteins within stress response pathways (e.g. p53, NF-B, heat shock response) are prominent features in many cancer types. Such alterations have been associated with poor response of tumors to conventional antitumor treatments. This is true for such cancers as non-small cell lung cancer, hepatocellular carcinoma, advanced prostate cancer, renal cell carcinoma and glioblastoma multiforme. Targeted therapies against these alterations may restore tumor response to treatment and, thus,improve clinical outcome. Multifunctional agents, such as the Curaxin to be studied in the context of this contract, have the potential to be more effective than drugs that target single pathways since they decrease the likelihood of tumors finding ways tocircumvent their effects unlike single function agents where one mutation or inactivation of a component of the targeted pathway would make tumors less sensitive to treatment.
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 288.03K | Year: 2016
PROJECT SUMMARY ABSTRACT Antiviral vaccines remain the largest segment of the rapidly growing global vaccine market Despite near complete eradication of poliovirus through vaccination efforts continued need for inactivated polio vaccine IPV is projected to reach million doses per year worldwide Among major obstacles to widespread use of the current IPV formulation are its high cost and insufficient potency to induce robust intestinal immunity Therefore development of an effective safe and affordable adjuvant for IPV that would allow reduction of the costly IPV antigen content represents a highly significant unmet need This Phase I SBIR proposal aims to address this challenge through optimization of a novel adjuvant system combining the immunostimulatory power of the toll like receptor TLR agonist entolimod previously CBLB with the well known adjuvant properties of Alum Entolimod is being developed for tissue protective anti radiation and supportive care in cancer treatment and anticancer immunotherapeutic applications by Cleveland BioLabs Inc CBLI and has an established safety profile Given the demonstrated adjuvant properties of the natural TLR agonist and entolimod parent flagellin investigators of this proposal in partnership with CBLI developed an innovative entolimod Alum based adjuvant system termed SA with advantages in terms of efficacy combined effect of two adjuvants versatility modular platform easily customized for many different antigen types and decreased futile adjuvant directed immunogenicity Preliminary studies confirmed that immunization of mice with IPV human dose co adsorbed on SA led to induction of increased levels of anti poliovirus neutralizing antibodies compared to immunization with IPV alone or IPV Alum Here we propose further optimization of entolimod as a co adjuvant through targeting of its residual immunogenicity and its ancillary inflammasome directed signaling activity Aim followed by characterization and optimization of the stability efficacy and safety of SA IPV formulations containing the identified optimal entolimod variant Aim In addition we will determine the impact of entolimodandapos s residual immunogenicity on adjuvant activity of SA via mapping and elimination of mouse T cell epitopes Together the deliverables of these aims will define and validate an optimal design for the SA platform and a new SA IPV formulation and set the stage for Phase II SBIR application and commercialization Project Narrative The proposed development of a novel modular and versatile adjuvant system combining a rationally optimized agonist of the TLR innate immunity receptor with Alum will address a significant medical need for potent safe and affordable poliovirus vaccine formulation and open additional opportunities on the rapidly growing global vaccine market
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 223.30K | Year: 2014
ABSTRACT: Radiotherapy is widely used to treat various types of cancer; however, its effectiveness is frequently limited by severe adverse effects resulting from radiation-induced damage to normal tissues in the tumor environment. Due to the scale of thisproblem and the current lack of safe and effective countermeasures against radiation toxicity, development of such agents is of broad significance for human health and presents an outstanding business opportunity. The new experimental drug CBLB502 is an agonist of mammalian Toll-like receptor 5 (TLR5) derived from its natural ligand, bacterial flagellin. CBLB502 is a powerful radioprotectant that was shown to selectively protect normal tissues, but not tumors, from radiation damage. In a recent study, CBLB502 effectively suppressed radiation-induced oral mucositis in a mouse model of head and neck cancer radiotherapy, while not reducing the antitumor efficacy of the radiation treatment. In fact, CBLB502 had a direct growth-suppressive effect on TLR5-express