Pang R.H.,Woomera Therapeutics, Inc.
Breast Cancer Research and Treatment
We demonstrate here that functional NMDAR1 and NMDAR2 receptors are expressed by Mcf-7 and SKBR3 breast cancer cell lines, and possibly by most or all high-grade breast tumors, and that these receptors are important for the growth of human breast cancer xenografts in mice. RT-PCR demonstrated mRNA for both NMDAR1 and NMDAR2 receptors are expressed in both Mcf-7 and SKBR3 cell lines, and these messages likely have sequences identical to those reported for human mRNAs. Proteins of the expected respective sizes 120 and 170 kD are generated from these mRNAs by the tumor cells. Cell growth was found to be significantly (P<0.0001) impaired down to 10% of normal growth by the irreversible NMDAR1 antagonists MK-801 and memantine with IC 50s ranging from 600 to>800 μM and from 200 to 300 μM for the two lines. Paradoxically, memantine with a lower binding affinity had the greater influence of the two inhibitors on cell viability. Immunohistochemical examination of highgrade invasive ductal and lobular breast cancer with our polyclonal antibodies against a peptide (-Met-Ser-Ile-Tyr-Ser-Asp-Lys-Ser-Ile-His-) in the extracellular domain of the NMDAR1 receptor gave specific positive staining for the receptor in all 10 cases examined. Positive staining was chiefly concentrated at the membranes of these tumor tissues. No staining with these antibodies was found for normal breast and kidney tissues. When Mcf-7 cells were grown as tumor xenografts in nu/nu mice, the growth of these tumors was completely arrested by daily treatments with MK-801 over 5 days. All of these data point to active NMDAR receptors being expressed by most breast cancers, and having an important influence on their survival. © Springer Science+Business Media, LLC. 2009. Source
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 149.82K | Year: 2014
DESCRIPTION (provided by applicant): There is currently no effective treatment for recurrent small-cell lung cancer (rSCLC). The objective of this project is to utilize a monoclonal antibody, MAG-1, to develop new, rational, and successful treatment of rSCLC. The hypothesis being tested is that a cancer -specific provasopressin antigen, called GRSA, present at the surface of these tumors will provide a sensitive, tumor-specific, and reliable target for the effective treatment by MAG-1 antibodies in combination with cyclophosphamide. Our preliminary data clearly show that treatment of variant SCLC tumor xenografts, with native and 90Yttrium-labelled mouse MAG-1 significantly slows growth, but this growth is almost completely impaired when antibody treatment follows cyclophosphamide. GRSA expression is a feature common to all, or most, SCLC and is absent from normal tissues. Phase 1 of this study is directed at advancing treatment of rSCLC using both mouse MAG-1 and already generated human chimeric MAG-1 a
Woomera Therapeutics, Inc. | Date: 2014-05-12
Provided herein are pro-VP antagonists, such as antibodies and antigen-binding portions thereof specific for pro-VP, for identifying and targeting expressing cancer cells. Applicants additionally provide methods of using said compositions, for example to image cancer cells in vivo and in biological samples. The compositions may also be used for treating patients suffering from a provasopressin-expressing cancer. Provasopressin-expressing cancers include neuroendocrine cancer, pancreatic cancer, and prostate cancer.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 688.43K | Year: 2009
DESCRIPTION (provided by applicant): The objective of this project is to utilize a monoclonal antibody, MAG-1, to develop new, rational, and successful treatment of breast cancer. The hypothesis being tested is that Glycopeptide-Related cell-Surface Antigen (GRSA) will provide a sensitive and reliable target for the effective treatment of breast cancer by MAG-1 and related antibodies. The data from the studies of Phase 1 of the project clearly show that short-term (6 day) MAG-1 treatment of both estrogen-responsive and estrogen-resistant (triple-negative) human breast tumor xenografts, can not only prevent growth of the tumors but produce large decreases in size. This was found for the unmodified antibody as well as for 90Yttrium-labeled antibody. More significantly, longer-term (16 day) treatment with unmodified antibody prevents tumor re-growth by inducing massive necrosis. Our earlier data show GRSA expression is a feature common to all, or most, breast cancers and DCIS. It also shows GRSA-like antigens can be targeted in patients with antibodies, and that our MAG-1 monoclonal antibody not only recognizes GRSA in all breast tumors but also targets GRSA in vitro. Phase 2 is directed at advancing treatment of breast cancer with MAG-1 by developing a human chimeric form (cMAG-1) of the mouse monoclonal antibody, and then a humanized form (hMAG-1). The ability of cMAG-1 and hMAG-1 to target and treat human breast cancer xenografts in mice will then be tested. Phase 2 goals are directed towards (i) generating a chimeric form (cMAG-1) of MAG-1with the constant regions of human IgG; (ii) establishing that the targeting, recognition, and treatment profiles of mMAG-1 are retained by cMAG-1; (iii) modeling a humanized form (hMAG-1) of MAG-1 from the cMAG-1 with genetically grafting CDRs from the VH and VL regions of mMAG-1 into the DNA framework of a human antibody; (iv) establishing that the targeting, recognition, and treatment profiles of mMAG-1 are retained by hMAG-1. These investigations will employ, RT-PCR, ligation, and cloning, DNA recombinance, DNA sequencing, immunohistochemistry, antibody modification, Northern and Western analysis with densiometric quantitation, ELISA, RIA, tumor-directed targeting, whole-body scintigraphy for 99mTechnetium, cytofluorographic and radiometric quantitation, radioligand binding, flow cytometry, CDC assay, ADCC assay, TUNEL assay, and cell and tumor growth assessments in nu/nu mice. A successful end-point of our Phase 2 studies would be the generation of cMAG-1and/or hMAG-1 forms of our antibody that show a similar binding affinity as mMAG-1, recognize all or most breast cancers, do not react with normal tissues, can reduce the size of tumors, and/or prevent their growth in vivo. The proposed research is expected to rapidly lead to new and successful therapeutic approaches for managing breast cancer. PUBLIC HEALTH RELEVANCE: With 217,440 new breast cancer patients per year, the identification of a novel cancer marker affords a unique opportunity to develop both diagnostic and therapeutic products to treat this disease. The proposed research is expected to lead to new and successful therapeutic approaches for managing breast cancer, thereby leading to a higher survival rate of the patients.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2011
DESCRIPTION (provided by applicant): The objective of this Phase 1 project is to improve an effective treatment of recurrent small-cell lung cancer (rSCLC) by targeting a tumor-specific abnormal receptor, AbnV2 that is a surface-marker of the disease. Currently, there is no effective treatment for rSCLC. Our data show expression of this abnormal vasopressin V2 receptor (AbnV2 ) is a common feature of recurrent as well as primary cancers, and can be targeted by polyclonal and monoclonal antibodies recognizing unique features in a C-terminal extracellular domain. They are absent from normal tissues. Polyclonal Abs can inhibit in vitro the growth of cancer cells derived from recurrent as well as primary tumors. Expression of such receptors therefore not only raises the possibility to develop new and successful therapies for this disease, but also methods for detecting residual tumor and monitoring treatment. Such therapies should have particular relevance to recurrent disease. The hypothesis being tested is that the AbnV2 receptor will provide a sensitive and reliable target for effective treatment of recurrent rSCLC, and that monoclonal antibodies can serve as effective therapeutic targeting agents. Phase 1 goals are directed towards:(i) performing a 'proof ofprinciple' evaluation of the effectiveness of unmodified and/or 90Y-labeled anti-AbnV2 monoAb to destroy/prevent growth of variant (and recurrent disease derived) NCI H82 and classical (and primary tumor-derived) NCI H345 SCLC cells grown in athymic mice;(ii) establishing the distribution and abundance in SCLC tumors of AbnV2 receptor protein and its unique expression by these tumors, and;(iii) determining the ability of anti-AbnV2 monoAb to inhibit the growth of SCLC cells in culture, and exploring mechanisms through which growth inhibition is accomplished. Treatment with forms of anti-AbnV2 monoAb will be compared with ubiquitous immunoglobulin (MOPC21). These investigations are designed to employ, tumor targeting in a mouse model, cytofluorographic and radiometric quantitation, antibody modification, tumor growth assessments, assessment of apoptotic and necrotic changes, IHC, ELISA, RIA, flow cytometry, RT-PCR, DNA sequencing, and Western analysis with densiometric quantitation. The approach employed is considered innovative because it represents the first treatment of form of recurrent SCLC cancer with an unmodified tumor-specific antibody. It is also provides the possibility that treatment progress can be monitored by use of radio-labeled fragments of the same antibody. A successful end-point of our Phase 1 studies would be the clear determination that unmodified, and/or 90Yttrium-labeled, anti-AbnV2 antibody can destroy or significantly curtail the growth of SCLC tumors in vivo, and that AbnV2 is a marker for gt50% of SCLC tumors. Phase 2 would involve the preclinical testing of chimeric and humanized forms of anti-AbnV2 on SCLC. The proposed research is expected to rapidly lead to new and successful therapeutic approaches for managing recurrent small-cell lung cancer. rSCLC resists all current efforts at treatment. PUBLIC HEALTH RELEVANCE: This project will introduce a new targeted therapeutic approach for the treatment of recurrent small-cell lung cancer, a disease that is refractory to all current treatments. This refractoriness means lt 10% expected 5 year survival rate for patients representing gt 40,000 new cases of SCLC that arise in the USA each year. Our targeted approach is directed at a newly discovered abnormal receptor which seems to be a tumor-specific surface marker of recurrent small-cell lung cancer. Targeting will employ an available monoclonal antibody to treat this deadly disease. This antibody recognizes a unique extracellular portion of the marker. Currently patients with recurrent SCLC usually succumb to the disease in 3 to 6 months. The proposed research is expected to lead to new successful therapies for managing recurrent SCLC, thereby leading to a higher long- term survival rate for these patients.