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Fiorino D.F.,Vertex Pharmaceuticals | Garcia-Guzman M.,Aspyrian Therapeutics, Inc.
Handbook of Experimental Pharmacology | Year: 2012

The antinociceptive and analgesic effects of muscarinic receptor ligands in human and nonhuman species have been evident for more than half a century. In this review, we describe the current understanding of the roles of different muscarinic subtypes in pain modulation and their mechanism of action along the pain signaling pathway, including peripheral nociception, spinal cord pain processing, and supraspinal analgesia. Extensive preclinical and clinical validation of these mechanisms points to the development of selective muscarinic agonists as one of the most exciting and promising avenues toward novel pain medications. © 2012 Springer-Verlag Berlin Heidelberg.

Maawy A.A.,University of California at San Diego | Hiroshima Y.,University of California at San Diego | Hiroshima Y.,Anticancer, Inc. | Hiroshima Y.,Yokohama City University | And 7 more authors.
Journal of Surgical Research | Year: 2015

Background Photoimmunotherapy (PIT) is based on the use of a monoclonal antibody specific to cancer epitopes conjugated to a photosensitizer near-infrared phthalocyanine dye (IR700). In this study, PIT with IR700 conjugated to anti-carcinoembryonic antigen (CEA) was used as an adjunct to surgery in orthotopically-implanted human pancreatic cancer in a nude mouse model to eliminate microscopic disease in the post-surgical tumor bed and prevent local as well as metastatic recurrence. Materials and methods Athymic nude mice were orthotopically implanted with the human pancreatic cancer cell line BxPC3 expressing green fluorescent protein. After tumor engraftment, the mice were divided into two groups as follows: bright light surgery (BLS) + anti-CEA-IR700 + 690 nm laser (PIT); and BLS only. Anti-CEA-IR700 (100 μg) was administered to the treatment group via tail-vein injection 24 h before therapy. Tumors were resected, and the surgical bed was treated with intraoperative phototherapy at an intensity of 150 mW/cm2 for 30 min. Mice were imaged noninvasively for 8 wk using an OV-100 small animal fluorescence imager. Results BLS + PIT reduced local recurrence to 1/7 mice from 7/7 mice with BLS-only (P = 0.001) and metastatic recurrence to 2/7 mice compared with 6/7 mice with BLS-only (P = 0.03). Local tumor growth continued at a rapid rate after BLS-only compared with BLS + PIT where almost no local growth occurred. There was a significant difference in tumor size between mice in the BLS + PIT (2.14 mm2, 95% confidence interval [CI] [-2.06 to 6.34] and BLS-only groups (115.2 mm2, 95% CI [88.8-141.6]) at 6 wk after surgery (P < 0.001). There was also a significant difference in tumor weight between the BLS + PIT group (6.65 mg, 95% CI [-6.35 to 19.65] and BLS-only group (1100 mg, 95% CI [794-1406] at 8 wk after surgery (P < 0.001). Conclusions PIT holds promise in the treatment of pancreatic cancer and may serve as a useful adjunct to surgery in the eradication of microscopic residual disease that can lead to both local and metastatic recurrence. Further studies are warranted to investigate the potential toxicities of PIT, especially with regard to anastomoses, such as those involved in pancreaticoduodenectomy. © 2015 Elsevier Inc. All rights reserved.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 416.56K | Year: 2011

DESCRIPTION (provided by applicant): The goal of this phase I SBIR proposal is to generate the pharmacokinetic and pharmacodynamic data required to support the filing of an Investigational New Drug application (IND) to the Food and Drug Administration (FDA), of the tumor-penetrating peptide iRGD, in combination with gemcitabine as a new treatment for pancreatic cancer. Pancreatic cancer is a key funding priority for the NCI in 2011. iRGD, increases drug accumulation and penetration specificaly into tumors,when co-administered with chemotherapeutic agents, enhancing anti-tumoral activity and tolerability. Pancreatic cancers are characterized by a dense extracellular matrix and stroma that together with high tumor interstitial fluid pressure, acts as a physical barrier inhibiting drug access to the tumor. Increasing drug access deep into the tumor is essential for improving the clinical outcome of both current and future therapies. Preliminary data show that co-administration of iRGD with gemcitabine, the first-line treatment for pancreatic cancer, augments anti-tumoral activity in a xenograft model of pancreatic cancer. The goal of this proposal is to complete the pharmacokinetic and preclinical efficacy studies required to enable filing of an IND for iRGDin combination with gemcitabine as follows: Phase I Aims: 1. Biodistribution studies and optimization of iRGD dosing in combination with gemcitabine. 2. Demonstrate enhanced anti-tumoral activity of gemcitabine co-administered with iRGD in a mouse model ofpancreatic cancer. Phase II of this proposal will focus on completion of the required toxicology studies necessary to support filing of an Investigational New Drug application with the Food and Drug Administration. We expect iRGD- based therapies to define the new standard-of-care in pancreatic cancer. The clinical validation of iRGD as a method to enhance anti-tumoral activity of drugs, will support a broader effort to combine iRGD with other anti- cancer therapies. PUBLIC HEALTH RELEVANCE: Poorpenetration of drugs into tumors has recently been recognized as a significant contributing factor to cancer drug resistance. This is particularly true of malignancies such as pancreatic cancer which are characterized by a desmoplastic microenvironment oflow microvascular density. Our collaborators have discovered a way of overcoming the drug penetration problem. The goals of this Phase I SBIR proposal is to conduct pre-clinical studies aimed at applying this new technology to the treatment of pancreatic cancer, and in the process, define a new standard of care for this deadly disease.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 417.54K | Year: 2011

DESCRIPTION (provided by applicant): Pain imposes a tremendous burden on society, costing approximately US 1 trillion per year in medical treatment, loss of productivity and disability payments in developed countries, not to mention the human suffering associated with moderate to severe acute and chronic pain. Current treatments are insufficient to address the challenge of acute and chronic pain. Narcotics pose a problem of addiction and safety risk while other types of analgesics (e.g. NSAIDs, COX2 inhibitors, antidepressants and anti-epileptics) are hampered by limited efficacy and acute or long-term side effects. Moreover, the recognition of the progressive nature of pain, with pain evolving into persistent allodynia and hyperalgesia due to the presence of chronic disease (e.g. inflammation) and plasticity of neuronal mechanisms involved in pain, calls for the development of novel analgesic treatments with disease modifying potential. Future therapies should address pain transmission (analgesic activity) while ameliorating the cause of pain (e.g. inflammation) and reversing the abnormal neuronal changes causing allodynia and hyperalgesia. The recent discovery that lipid-mediators called resolvins, activate ChemR23 G-protein coupled receptors to induce analgesia, ameliorate inflammation, and reverse neuronal plasticity associated with chronic pain presents a unique opportunity to develop therapies with transformational potential. We propose an innovative approach to identify novel ChemR23 small molecule agonists by using new functional screening technologies based on label free formats, and signal transduction analysis to select and optimize molecules with optimal pharmacological profiles. Given the clinical validation of resolvins as anti-inflammatory ligandsand the correlation of ChemR23 mechanisms of analgesia with processes of clinical relevance, ChemR23 agonists may represent a novel new class of analgesics to treat acute and chronic pain conditions. PUBLIC HEALTH RELEVANCE: There is a critical medical need to develop novel treatments for pain that are safe and induce effective analgesia while reversing the pathology causing hyperalgesia and allodynia. This proposal details a new approach to develop novel pain treatments based on a new mechanism ofaction that has the potential to induce analgesia, ameliorate inflammation and reverse neuronal alterations that lead to and sustain chronic pain. Drug products developed in this program could be transformative in pain management with the potential of disease modifying actions in chronic pain.

News Article | April 23, 2015
Site: www.xconomy.com

It comes as no surprise that federal grants for innovative research or technology transfer have become a lifeline for many early stage life sciences startups in the San Diego area. What may be surprising, though, is the extent of such funding, and the number of local biotech and medical device companies that have gotten Small Business Innovation Research (SBIR) or Small Business Technology Transfer (STTR) grants over the past decade. Since 2005, the multi-agency National Institutes of Health alone has awarded more than $364 million in grants to at least 230 life sciences companies in the San Diego area, according to a review of innovation grant data by Xconomy and GrantIQ, a Santa Monica, CA, startup that aggregates public information on federal research and innovation funding. Casting a wider net to include funding from other federal agencies (Congress authorized 12 agencies to award innovation grants), GrantIQ reports that over $570 million has been awarded to companies throughout the San Diego area through 1,905 innovation grants. At my request, GrantIQ developed a public report for Xconomy that lists the 230 San Diego life sciences companies that received SBIR or STTR grants from the NIH. The interactive report, available online here, enables users (who can register for a free trial period) to search for information about grants awarded to each of the 230 companies over the past decade. GrantIQ operates SBIRsource.com, a subscription-based website that provides data, analytics, and insights about innovation funding. The list is a trove of unsung startups that represent a coming wave of life sciences innovation in San Diego, led by Prognosys Biosciences, a next-generation genome sequencing and analytics company that has been operating in stealth mode for 10 years. Other up-and-coming startups on the list are Genalyte, a startup developing photonic technology on a chip to perform as many as 128 diagnostic tests on a single drop of blood; Epigen Biosciences, a collaborative startup applying a host of drug discovery tools to reach proof-of-concept faster; Novoron Bioscience, a two-year-old startup developing new drugs for nerve regeneration; Aspyrian Therapeutics, an anti-cancer startup that uses near-infrared light to activate antibody conjugates; and Sirenas Marine Discovery, a four-year-old startup identifying new small molecule drugs from marine organisms. CEO Darren Rush said he co-founded GrantIQ with Chris Jones, director of strategic technology development at Bedford, MA-based iRobot, in 2012. “We leveraged a lot of Chris’s program knowledge, as he led iRobots’ SBIR efforts until the point they no longer qualified as a ‘small’ business, CEO Darren Rush said. GrantIQ’s customers “are more and more, larger organizations who use the SBIR programs as a hunting ground for new technologies to license, acquire, or partner,” Rush said. Altogether, federal agencies dispense roughly $2.5 billion each year through innovation grants. On its website for the program, the NIH says it will invest over $780 million through innovation grants this year to early stage life sciences companies. A key objective is commercializing … Next Page »

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