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BUFFALO, NY, United States

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: | Program: SBIR | Phase: Phase I | Award Amount: 130.69K | Year: 2009

DESCRIPTION (provided by applicant): Advances in treatment strategies have increased the long-term survival of children with acute lymphoblastic leukemia (ALL). However, the outlook of infants with ALL remains dismal with long-term survival rates of only 30-50%. Therefore, new treatments are desperately needed. Translocation of the mixed lineage leukemia (MLL) transcription factor is found in 70-80% of infant ALL cases and is associated with poor treatment outcome, suggesting that targeting MLL may have clinical benefit. Through cell-based small molecule screening, we identified small molecule SM7, which specifically kills multiple types of MLL-leukemia with little effect on non-MLL cancers or normal cells, including those of hematopoietic origin. However, maximum killing is achieved at 10 ?M and molecule appears to be structurally unstable. Therefore, the goal of this proposal is to structurally optimize SM7 for both efficacy and stability using synthetic chemistry guided by stability testing and MLL-specificity characterization in order to generate a potential lead compound(s) for development into an anticancer drug for the treatment of MLL-leukemia. PUBLIC HEALTH RELEVANCE: Infant acute lymphoblastic leukemia often contains MLL gene translocations (70-80%), which are associated with poor treatment response. There is currently no effective treatment due to the lack of efficacy of current available drugs and severe toxic side effects caused by highly intensive therapy. Development of an MLL-leukemia specific drug should provide a more efficacious and less toxic alternative to current treatment strategies and, thus, has major implications for the therapeutic management for all children with this aggressive disease.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 104.61K | Year: 2009

DESCRIPTION (provided by applicant): One of the major problems in the fight against cancer is the intrinsic or acquired resistance of tumors to current cancer treatments, particularly that associated with multidrug transporters (MDT; e.g. P-glycoprotein (P-gp) and the multidrug associated protein (MRP1)). The clinical failures of early P-gp inhibitors, which either caused non-specific toxicity or pharmacokinetic interactions with conventional chemotherapy agents, has significantly diminished the enthusiasm of pharmaceutical companies to develop MDT inhibitors. Nevertheless, drug resistance associated with these transporters is still a serious problem and the development of inhibitors against these proteins must be revisited using the knowledge and experience gained from previous failures to significantly increase the chances for success. The studies outlined in this proposal center around the optimization of Reversan, a MRP1 inhibitor that surpasses the activity of many known inhibitors of this MDT in the absence of toxicity. Our goal is to develop Reversan as an anti-cancer agent to be used together with standard chemotherapy to improve the efficacy of these conventional agents using liposomal formulations of Reversan or Reversan-drug combinations. Liposomal vehicles for in vivo delivery offer important features for tumor delivery of molecules, including decreased systemic clearance rates, decreased systemic toxicity as a result of decreased uptake of formulated agents by normal tissues and at the same time improved efficacy due to increased uptake of the formulated agents by tumors. The data generated under this proposal will form the basis for the rational design of studies involving other conventional agents as well as for clinical trials using Reversan combinations to assess the potential of Reversan as an anti-cancer agent. The significance of this project lies in its potential for identifying new treatment strategies for drug refractory cancers, such as neuroblastoma, that are currently faced with limited treatment options due to inherent and acquired drug resistance caused by MRP1 or MDTs in general. PUBLIC HEALTH RELEVANCE: One of the major problems in the fight against cancer is resistance to current cancer treatments, particularly resistance caused by multidrug transporters that pump standard cancer drugs out of cancer cells. Inhibitors of these transporters, such as Reversan-the focus of this proposal, when used together with standard chemotherapy should greatly increase the killing of tumor cells by allowing the drugs to stay in tumor cells. Thus, Reversan has the potential to improve the clinical outcome for patients with limited treatment options due to multidrug resistance.

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

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