Ramesh B.,A And G Pharmaceutical, Inc. |
Bhalgat C.M.,A And G Pharmaceutical, Inc.
European Journal of Medicinal Chemistry | Year: 2011
In the present study, we have synthesized novel dihydropyrimidines (1a-j), their dimethylated adducts (2a-j), and hydrazine derivatives (3a-j) of 2a-j and subsequently their pyrazole derivatives (4a-j). Elemental analysis, IR, 1H NMR and mass spectral data elucidated structure of newly synthesized compounds. Some of these novel derivatives showed moderate to potent in vitro antioxidant, anti-inflammatory, antibacterial, antifungal and anthelmintic activity. © 2011 Elsevier Masson SAS. All rights reserved.
Kumar T.,A And G Pharmaceutical, Inc. |
Research Journal of Medicinal Plant | Year: 2011
The use of natural products as medicinal agents presumably predates the earliest recorded history. Bauhinia purpurea is a species of flowering plant is used in several traditional medicine systems to cure various diseases. This plant has been known to possess antibacterial, antidiabetic, analgesic, anti-inflammatory, anti-diarrheal, anticancerous, nephroprotective and thyroid hormone regulating activity. A wide range of chemical compounds including 5,6-Dihydroxy-7-methoxyflavone 6-0- β -D xylopyrano-Side, bis [3',4'-dihydroxy-6-methoxy-7,8-furano-5',6'-mono-methylalloxy]-5-C-5-biflavonyl and (4'-hydroxy-7-methyl 3-C-α-L-rhamnopyranosyl)-5-C-5-(4'-hydroxy-7- methyl-3-C-α-D-glucopyranosyl) bioflavonoid, bibenzyls, dibenzooxepins, mixture of phytol fatty esters, lutein, β-sitosterol, isoquercitin and astragalin etc. The present review discusses phyto-chemistry, pharmacology, medicinal properties and biological activity of B. purpurea and its usage in different ailments. © 2011 Academic Journals Inc.
A And G Pharmaceutical, Inc. | Date: 2011-08-29
Disclosed herein are compositions and methods for reducing the growth of hematopoietic malignant cells (e.g., B-cell leukemia cells). The methods involve reducing the growth of hematopoietic malignant cells by contacting hematopoietic malignant cells with GP88 antagonists. GP88 is an 88 KDa autocrine growth factor that promotes the growth of hematopoietic malignant cells. Antagonists to GP88 are provided which inhibit its expression or biological activity. The antagonists include antisense oligonucleotides and antibodies. Also provided are methods for determining if a patient is responding or is responsive to anti-cancer therapy (e.g., glucocorticoid therapy). Increased levels of GP88 in hematopoietic cells indicates a patient is not responding or responsive to anti-cancer therapy.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 113.32K | Year: 2011
DESCRIPTION (provided by applicant): 40,000 women die annually in the US as a result of breast cancer (BC). Although BC can be controlled if detected early, a significant number is not detected until later and these patients are treated using therapies tocontrol both primary tumor and micro-metastatic disease. Therapy response is monitored using imaging and clinical assessment. Failure to detect early progression is a missed opportunity to adopt suitable therapies at a time when their impact on the diseasecan be maximized. Identification and validation of surrogate markers for identification of disease progression would provide clinicians with timely information in the management of BC therapy. The purpose of this application is to investigate the performance characteristics of the novel 88kDa autocrine growth factor GP88 as a surrogate marker for disease progression in breast cancer patients. GP88 is a critical biological driver for proliferation, survival, and invasiveness and is over expressed in invasive ductal cancers while negative in benign lesions and normal breast tissue. Two tests were developed to measure GP88 expression in cancer specimens; an IHC test for tumor biopsies and an EIA to measure circulating GP88 in biological fluids that have been validated in clinical trials. Tissue GP88 expression was predictive marker of BC recurrence while serum GP88 was elevated in BC patients with progressive disease, but not in BC patients with no evidence of disease. The specific aims of this revised SBIR Phase I are to investigate GP88 as a surrogate marker for disease progression in BC patients enrolled in the I-SPY Trial. The I-SPY trial is a national study to identify biomarkers predictive of response to therapy throughout the treatment cycle for women with Stage 3 breast cancer in neoadjuvant setting. This trial enrolled 221 patients with tissue and serum samples collected at specific time points pre and post-treatment and subjects followed for three years post-therapy. 122 (55%) patients benefited from neo-adjuvant treatment, 40 (18%) patients received some benefit (tumors reduced by 10% - 40%) and 59 (27%) patients showed no benefit (disease progressed). Aims are: 1: Determine if serum/tissue GP88 levels are a surrogate marker to identify breast cancer patients not benefiting from on-going neo-adjuvant chemotherapy. We will determine if there is a correlation between GP88 level and decreased/increased tumor volume in chemo-naive patients undergoing neo-adjuvant chemotherapy. 2: Determine if serum GP88 canbe used to identify breast cancer patients most likely to have recurrence following an initial benefit from neo-adjuvant therapy. We will determine if there is a quantifiable difference in the risk of recurrence between those patients with high and low serum or tissue GP88 levels, prior to commencing neo-adjuvant therapy. Upon completion of these specific aims, this investigation will evaluate GP88 as a surrogate to identify disease progression in patients undergoing chemotherapy and additionally if initialserum GP88 level prior to commencing therapy is correlated to risk of recurrence and will provide additional tools to clinicians to monitor therapy response and disease progression during and after treatment. PUBLIC HEALTH RELEVANCE: (Lay) Breast cancer (BC) incidence in US women is second only to lung cancer and is one of the leading causes of cancer related death; 40,000 women die annually. Patients in whom BC is detected as having spread beyond the breast are treated with radiation, chemotherapyand/or hormonal therapy prior to potential surgery. During and post treatment, tumor response is monitored using x-ray and clinical evaluation, imprecise methods for detection of subtle changes in tumor size that may indicate treatment failure. Use of X-ray imaging is relatively infrequent, subjective and requires availability of prior studies. There are no easily available specific diagnostic markers, direct or surrogate, for monitoring disease activity in BC. We have identified GP88 as a biomarker that may be used as a surrogate for detection of tumor changes in BC patients undergoing therapy. Preliminary data in a small study demonstrated that GP88 can be identified in serum of BC patients and is elevated in patients with progressive disease but not in patients with no evidence of disease following therapy, thus indicating that it may be useful as a surrogate marker for assessing response to chemotherapy. This project will investigate the use of GP88 as a surrogate marker for detection of non-response tochemotherapy and will provide information that may enable clinicians to adopt 2nd or 3rd line therapies when they may be most effective and may save patients un-necessary toxicity and costs associated with ineffective 1st line therapy.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 199.38K | Year: 2012
Aromatase Inhibitors (AI) are the preferred hormonal treatment for estrogen receptor positive Breast Cancer (BC) in postmenopausal women and are used to treat approximately 140,000 patients annually in the US. However, ~40% of patients will be, or become resistant to AIs. If sensitivity to AI can be re-established in patients that have become resistant, this would be a major step forward in treating ER+ BC patients. The PI has characterized a growth factor, GP88, and demonstrated its critical role in the development, proliferation and survival of cancer cells. Importantly, the PI has demonstrated using in vitro studies that GP88 is a driver in controlling cancer cell resistance to AIs such as Letrozole. The PI has developed a neutralizing monoclonal anti-GP88 antibody, shown in vitro to return BC cell sensitivity to AIs in previously AI resistant cell lines. This application seeks to prove through the use of xenograft studies that anti-GP88 is effective in vivo in restoring AI sensitivity in previously resistant tumors. If successful, anti-GP88 in conjunction with AI therapy in AI resistant patients would be a major advancement in treating BC patients that currently have systemic chemotherapy as their only option and could improve overall BC survival.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 199.83K | Year: 2013
The purpose of this application is to develop realiable, renewable, cost effective, specific, high affinity antipeptide affitnity reagent to be successfully used in mass spec based cancer biomarker detection methods such as SISCAPA, for the analysis of patient plasma. Early detection of cancer is a key to successful and cost effective treatment. Routine monitoring of the plasma biomaker levels is a non-invasive method for screening for cancer and monitoring for recurrence after treatment. SISCAPA is one such technology that allows the monitoring of biomarker levels in the plasma of healthy and diseased individuals. In order to detect the presence of relevant biomarker levels in the plasma, high affinity highly specific anti-peptide capture reagents must be developed. In this application we propose to develop, high affinity monoclonal antibodies to 10 biomarker peptides to be successfully used in SISCAPA application as a proof of concept. The goal is to provide a reliable innovative platform technology that can consistently, efficiently, and cost effective generate high quality renewable anti-peptide cancer biomarker reagents. PUBLIC HEALTH RELEVANCE
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.00M | Year: 2015
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 193.88K | Year: 2012
DESCRIPTION (provided by applicant): Lung Cancer remains the leading cause of cancer and mortality for men and women worldwide. In 2010, there were 222,520 new cases of lung cancer diagnosed in the US, 85% being non small cell lung cancer (NSCLC) and157,300 lung cancer related deaths. Clearly, there is a need for additional and novel therapeutic options. The use of anti-EGF-R and anti v-EGF therapies has proven the potential of targeted therapies and monoclonal antibody approaches. The development ofnovel therapy against target critical and specific to the cancer cells but not to the normal tissues is expected to be efficacious and minimize damage to healthy cells. AandG Pharmaceutical Inc. is focused on identifying theranostic target for cancer in order to develop biological targeted therapy with companion diagnostics. These activities have led to the discovery of the 88 kDa granulin precursor (GP88), an autocrine growth factor preclinically validated as playing a role in NSCLC tumorigenesis. We haveshown that: 1) GP88 is an autocrine growth/survival factor for NSCLC; 2) increased GP88 expression in NSCLC positively correlates with increased tumorigenic properties of NSCLC; 3) GP88 mediates tumor cell angiogenesis and invasiveness; 4) NSCLC overexpressing GP88 are resistant to current therapies; 5) increased GP88 expression in malignant tissue correlates with parameters of poor prognosis while normal tissue is negative; 6) high expression of GP88 is associated with increased risk of recurrence in earlystage NSCLC; 7) lung cancer patients with poor prognosis have elevated GP88 serum levels; 8) a neutralizing anti-human GP88 monoclonal antibody (AG1) has been developed in our laboratory and been validated previously in our breast cancer xenograft system.Preliminary results using NSCLC indicated that AG1 abrogates GP88 functional activity. The phase I SBIR application focuses on fully characterizing AG1 effect on NSCLC xenografts. The specific aims are: 1) Determine the efficacy and potency of anti-humanGP88 monoclonal antibody AG1 in mono-therapy for non small cell carcinoma in nude mice xenograft models. We will determine the optimal therapeutic dose of AG1 in xenograft models with H1299 and A549 cells widely used as NSCLC models; 2) Determine the effect of AG1 antibody in combination therapy with chemotherapeutic agents (docetaxel, cisplatin and gemcitabine) that are used in the standard of care for NSCLC. Initially, optimal therapeutic dose for docetaxel, cisplatin and gemcitabine will be determined using A549 and NCI-H1299 xenografts in a monotherapy regimen. We will determine if AG1 combined with each chemotherapeutic drug will potentiate its effect. At the conclusion of this Phase I, we will have demonstrated whether GP88 is a candidate for NSCLC targeted therapy and established the optimal therapeutic effects of AG1 for NSCLC. If successful, such novel therapy will have the potential to improve treatment and increase the survival outcomes and quality of life of NSCLC patients. PUBLIC HEALTHRELEVANCE: Lung Cancer remains the leading cause of cancer and mortality for both men and women worldwide. AandG Pharmaceutical Inc. has discovered a novel target that plays a critical role in tumor growth, survival and resistance to current therapies. The laboratory has developed agents that can block the action of this growth factor on tumor formation. The present application proposes feasibility studies to investigate if this agent can be inhibit lung cancer, particularly on small cell lung carcinoma. At the end of this phase I SBIR study, we will have established feasibility studies to develop novel therapies for lung cancer.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.48M | Year: 2014
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.15M | Year: 2010
DESCRIPTION (provided by applicant): Breast cancer remains one of the top three cancers to affect and cause mortality in women. Major shortcomings with current treatment are the high level of side effects induced in patients and insufficient efficacy, particularly for patients with metastatic disease. Targeted cancer therapy is designed to treat only the cancer cells and minimize damage to healthy cells. These targets are critical to the tumor's malignant phenotype but not to the host's normal tissues, improving outcomes while minimizing systemic side effects. Anti-HER2, Herceptin, leads the way for targeted therapy in breast cancer with a much lower incidence of side effects and definite efficacy in a specific but small subset of patients. However, there is a clear need for additional therapeutic options including other novel targeted therapies. The 88 kDa autocrine growth factor called PC-Cell Derived Growth Factor (PCDGF), also known as granulin precursor (GP88), has been shown to play a critical role in breast cancer cell biology, exemplified by the following: 1) GP88 is an autocrine growth/survival factor for breast cancer cells, 2) increased GP88 expression in breast cancer cells is associated with increased tumorigenicity, 3) GP88 mediates tumor cell angiogenesis and invasiveness, 4) breast cancer cells overexpressing GP88 are resistant to current therapies - Tamoxifen, Faslodex, doxorubicin, 5) increased GP88 expression in breast cancer tissue correlates with clinical parameters of poor prognosis while normal and benign breast tissue are negative, 6) patients with poor prognosis have elevated GP88 serum levels. These experiments show the essential role that GP88 plays in breast cancer cell tumorigenesis and that the inhibition of GP88 expression or function leads to inhibition of tumor growth. These results highlight the importance of GP88 for targeted therapy of breast cancer via the development of anti-GP88 therapeutic neutralizing monoclonal antibodies (Mabs). Our Phase I research proposed to evaluate a library of murine anti-GP88 for antigen binding properties and for biological activity in GP88-dependent in vitro and in vivo functional tumor cell models. These Phase I specific aims were accomplished and resulted in the identification of anti-GP88 neutralizing Mabs with the in vitro and in vivo potency and efficacy to be candidates for targeted therapy in breast cancer to address a vitally important unmet clinical need. We have selected one Mab, AG1, for further pre-clinical development activities, specifically the generation and characterization of a recombinant Mab (chimerized and humanized Mabs). The following Specific Aims are proposed for this Phase II SBIR application: 1. Cloning of the cDNA encoding the variable sequences of the light chain and heavy chain of the antibody expressed by the AG1 hybridoma cells and generation of expression vectors for both a humanized (HuAG1) and a mouse-human chimeric antibody (ChAG1). 2. Transient expression of the HuAG1 and ChAG1 chimeric antibodies and validation of their binding properties. The antigen binding characteristics and biological activities of the cloned, expressed HuAG1 and ChAG1 will be evaluated and compared with the murine AG1 Mab in order to select candidate recombinant AG1 that fit acceptance criteria for further development. 3. Generate stable HuAG1- or ChAG1-producing cell clones. HuAG1 or ChAG1 selected above will be stably expressed in CHO cells. The HuAG1- or ChAG1-producing clones will be compared for cell growth performance, antibody productivity, and metabolic profile in order to select a candidate clone for scale-up production. 4. Express, purify and characterize the biological properties of the HuAG1 or ChAG1 Mab. The Mab will be evaluated in relevant in vitro and in vivo functional tumor cell models and compared directly with the murine AG1 Mab. GP88 represents a novel, pre-clinically validated target for breast cancer. At the conclusion of this research in this Phase II project, we will have generated a mouse/human chimeric Mab with the in vitro and in vivo pre-clinical efficacy and potency for targeted therapy of breast cancer and we will have developed an optimized clonal antibody production cell line suitable for transfer to a CMO for contract manufacturing. However, once this chimeric anti-GP88 Mab has been generated and characterized it will require further pre-clinical development activities (e.g. formulation, pharmacokinetics and safety) before IND filing for clinical trials in breast cancer. These additional development activities will serve as the basis for a subsequent continuation/renewal Phase II SBIR application. PUBLIC HEALTH RELEVANCE: Breast cancer remains one of the top three cancers to affect and cause mortality in women. Major shortcomings with current treatment are the high level of side effects induced in patients and insufficient efficacy, particularly for patients with advanced disease. The innovative breast cancer therapy to be developed in this proposal will target a mechanism inherent in breast cancer but avoid the side effects associated with many current breast cancer therapies.