Woodinville, WA, United States

Cancer Targeted Technology, Llc

www.cancertargetedtechnology.com
Woodinville, WA, United States
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Patent
Cancer Targeted Technology, Llc | Date: 2016-08-24

Compounds as defined herein are provided which are useful in (1) diagnostic methods for detecting and/or identifying cells presenting PSMA; (2) compositions comprising a compound of the invention together with a pharmaceutically acceptable diluent; and (3) methods for imaging prostate cancer cells.


Liu T.,Washington State University | Wu L.Y.,Washington State University | Berkman C.E.,Washington State University | Berkman C.E.,Cancer Targeted Technology, Llc
Cancer Letters | Year: 2010

Prostate-specific membrane antigen (PSMA), an established enzyme-biomarker for prostate cancer, has attracted considerable attention as a target for imaging and therapeutic applications. We aimed to determine the effects of PSMA-targeted photodynamic therapy (PDT) on cytoskeletal networks in prostate cancer cells. PSMA-targeted PDT resulted in rapid disruption of microtubules (α-/β-tubulin), microfilaments (actin), and intermediate filaments (cytokeratin 8/18) in the cytoplasm of LNCaP cells. The collapse of cytoplasmic microtubules and the later nuclear translocation of α-/β-tubulin were the most dramatic alternation. It is likely that these early changes of cytoskeletal networks are partly involved in the initiation of cell death. © 2010 Elsevier Ireland Ltd.


Liu T.,Washington State University | Wu L.Y.,Washington State University | Choi J.K.,Washington State University | Berkman C.E.,Washington State University | Berkman C.E.,Cancer Targeted Technology, Llc
International Journal of Oncology | Year: 2010

The limitation of specific delivery of photosensitizers to tumor sites, represents a significant shortcoming of photodynamic therapy (PDT) application at present. Prostate-specific membrane antigen (PSMA), a validated biomarker for prostate cancer, has attracted considerable attention as a target for imaging and therapeutic applications for prostate cancer. The present study focuses on the investigation of a PSMA inhibitor-conjugate of pyropheophorbide-a (Ppa-conjugate 2.1) for a targeted PDT application and the mechanism of its mediated-cell death in prostate cancer cells. Multiple fluorescence labeling methods were employed to monitor PDT-treated prostate cancer cells by confocal laser scanning microscopy. Our results demonstrate that Ppa-conjugate 2.1 mediated apoptosis is specific to PSMA+ (positive) LNCaP cells, but not PSMA- (negative) PC-3 cells. Furthermore, these results indicate that following PDT, the activation of caspase-8, -3, -9, cleavage of poly(ADP-ribose) polymerase (PARP) and DNA fragmentation is sequential. The appearance of cleaved ß-actin further supported involvement of caspase-3. Specific caspase inhibitor blocking studies reveal that the caspase-8/-3 cascade pathway plays a key role in apoptosis of LNCaP cells induced by Ppa-conjugate 2.1. The demonstrated selective targeting and efficacy of this agent suggests that targeted PDT could serve as an alternative treatment option for prostate cancer.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 307.64K | Year: 2010

DESCRIPTION (provided by applicant): PSMA is an important biomarker for prostate cancer prognosis and an appropriate target for therapy due to its restricted expression mainly on late-stage, androgen-independent and metastatic prostate cancer cells. While currently there is only one clinical PSMA targeted agent for SPECT imaging (the antibody-based Prostascint ), high-affinity small-molecule inhibitors to PSMA have not been fully exploited for targeting and imaging prostate cancer. The overall objective of this application is to optimize a novel imaging probe for the in vivo detection of PSMA positive prostate tumors. Our central hypothesis for the proposed work is that an F-18 labeled irreversible inhibitor to PSMA coupled with PET scan could be used for prostate cancer staging as well as localization of lymph and bone metastasis. The rationale for undertaking the proposed research is that optimized F-18 labeled PSMA imaging constructs will serve as the foundation for a clinically relevant imaging modality for the diagnosis and post-treatment assessment of prostate cancer. This labeling needs to be in a chemistry that is readily available to the growing number of hospitals with cyclotrons and PET scanners. Additionally, demonstrating the effectiveness of our prostate tumor imaging probes in vivo and safety in animal models will serve as initial steps for the subsequent development of a radiotherapeutic agent for clinical use. The PIs will test the central hypothesis and accomplish the overall objective of this application by pursuing the following specific aims: Phase I 1) optimize the nucleophilic 18F labeling of CTT-54; 2) chemical/biochemical evaluation of lead compounds from AIM 1. Phase II Aims: 1) In vivo evaluation of selected PET tracers produced by Phase I and In vivo testing of lead compound for safety and pharmacokinetics Milestones include: labeling of CTT-54 with 1) an overall yield of 40%, high specific activity (gt500 Ci/mmole), stability of gt90% for up to 6 hours, 2) targeting of prostate cancer in mouse xenograft model and 3) a safety profile that will support filing an IND. The proposed work is expected to yield the following outcomes. First, a labeling chemistry that can be used in any one of the 277 PET centers in the United States. Secondly, a safety profile of the labeled lead compound that would support an investigation new drug application with the FDA. The high- affinity small-molecule targeting platform upon which our lead compound is based is unique compared to other targeting molecules because it has demonstrated irreversible binding to the prostate tumor biomarker PSMA. These unique characteristics make this compound is a more attractive targeting platform for prostate tumor binding with enhanced translational potential. It is expected that the proposed work will result in optimized prostate cancer imaging agents, which is important because better detection agents are essential for assisting clinicians in staging prostate cancer, developing personalized therapy, and monitoring treatment. PUBLIC HEALTH RELEVANCE: The overall goal of this application is to develop a novel clinically relevant diagnostic for prostate cancer that capitalizes on the potency and specific affinity of small-molecule inhibitors to PSMA. The overall objectives of this application are to further the development our primary PSMA inhibitor, CTT-54 by optimizing the 18F-labeling chemistry, demonstrating PET imaging of prostate cancer in animal models systems, and initiate toxicology studies in support of clinical trials. The preliminary data presented demonstrates that a small molecule inhibitor of PSMA can target and image prostate cancer when coupled to a radionuclide tracer.


Patent
Cancer Targeted Technology, Llc | Date: 2012-06-13

Compounds as defined herein are provided which are useful in (1) diagnostic methods for detecting and/or identifying cells presenting PSMA; (2) compositions comprising a compound of the invention together with a pharmaceutically acceptable diluent; and (3) methods for imaging prostate cancer cells.


Patent
Cancer Targeted Technology, Llc and Washington State University | Date: 2014-03-14

Compounds of Marlush formula (I) described in the claims are useful in diagnostic methods for detecting and/or identifying cells presenting PSMA. Disclosed are also methods for preparing the compounds. Representative compounds according to the application are:


Patent
Cancer Targeted Technology, Llc | Date: 2010-01-22

Compounds of the formula, A-L-B, wherein A is glutamate or a glutamate analog; L is a phosphoramidate or a phosphoramidate analog; and B is serine or a serine analog are described which are potent inhibitors of prostate-specific membrane antigen (PMSA). Such compounds are useful in treatment of prostate cancer; and when chemically attached to a fluorescent dye, can efficiently and selectively label prostate cancer cells for fluorescent imaging.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 2.00M | Year: 2015

DESCRIPTION provided by applicant Prostate cancer PCa is the most commonly diagnosed cancer and second leading cause of cancer death in American men The utility of the widely accepted diagnostic test for PCa the PSA test has come under severe scrutiny as only of men with PCa have levels that fall within the current PSA reference range Elevated PSA levels are not correlated well with the stage of PCa and a significant number of men are exposed to unnecessary surgery and radiation therapy with concomitant risks and detrimental side effects Molecular imaging of PCa is an increasingly important component for diagnosis staging and treatment of the disease However the FDA has approved only one diagnostic agent for PCa since ProstaScintandquot a mouse monoclonal antibody While the marker that ProstaScintandquot recognizes prostate specific membrane antigen PSMA is ideal as a biomarker ProstaScintandquot binds an intracellular epitope rendering it unable to detect living PCa cells As a result diagnostic accuracy of less than has led to poor adoption of this imaging test by oncologists PSMA a transmembrane protein has been described as an ideal biomarker for PCa diagnosis and targeted therapy as it is expressed mainly in PCa with a prevalence of andgt has high expression levels at all stages of the disease and is upregulated in androgen insensitive and metastatic disease is accessible on the cell surface and not shed into the circulation and is internalized after ligand binding To address the unmet need for accurate and quantitative imaging of PCa we will advance our novel proprietary low molecular weight PSMA inhibitor that selectively delivers an imaging radionuclide to PCa cells This small molecule inhibitor CTT binds PSMA irreversibly at an IC of less than nM In addition CTT and its F imaging payload is internalized into PSMA expressing cells in less than minutes This irreversible binding and rapid internalization makes this molecule unique amongst PSMA inhibitors that are in development and allows for excellent biodistribution and tumor uptake In addition we are pursuing the more sensitive and quantitative diagnostic imaging modality of PET as opposed to SPECT using a F labeled radiotracer In this grant we will advance the development of our PET imaging agent CTT by completing the cGMP manufacture and automated radiolabeling of Phase I clinical material in Aim In Aim we will establish a human safety profile as well as visualize PCa lesions and determine optimal imaging parameters and dosimetry in a Phase I clinical trial in PCa patients PET imaging using our F labeled PSMA inhibitor CTT will allow for rapid and sensitive assessment of proximal and distal manifestations of PCa something which is currently unavailable PUBLIC HEALTH RELEVANCE Prostate cancer is the most frequently diagnosed malignancy in men in the US and is the second leading cause of cancer related death in men The current standard of diagnosis the PSA test correlates poorly with disease progression and treatment outcomes New and exciting treatments are emerging for metastatic prostate cancer yet because of our current dependence on the PSA test it is not clear when it is best to prescribe these treatments The overall goal of this project is to further the manufacturing and clinical development of a non invasive PET diagnostic product that can be imaged within a few hours and is expected to specifically and sensitively image both the location and extent of both early cancer escaped from the prostate as well as distal metastatic cancer including bone metastases something that all current urine serum markers and current MRI and CT scans are unable to do In addition this PET imaging agent will help determine the need for certain treatments avoiding unnecessary exposure to detrimental side effects and will effectively monitor and modify treatment regimens to achieve maximal efficacy


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2015

Not Available


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.15M | Year: 2011

DESCRIPTION (provided by applicant): PSMA is an important biomarker for prostate cancer prognosis and an appropriate target for therapy due to its restricted expression mainly on late-stage, androgen-independent and metastatic prostate cancer cells. Whilecurrently there is only one clinical PSMA targeted agent for SPECT imaging (the antibody-based Prostascint ), high-affinity small-molecule inhibitors to PSMA have not been fully exploited for targeting and imaging prostate cancer. The overall objective ofthis application is to optimize a novel imaging probe for the in vivo detection of PSMA positive prostate tumors. Our central hypothesis for the proposed work is that an F-18 labeled irreversible inhibitor to PSMA coupled with PET scan could be used for prostate cancer staging as well as localization of lymph and bone metastasis. The rationale for undertaking the proposed research is that optimized F-18 labeled PSMA imaging constructs will serve as the foundation for a clinically relevant imaging modality for the diagnosis and post-treatment assessment of prostate cancer. This labeling needs to be in a chemistry that is readily available to the growing number of hospitals with cyclotrons and PET scanners. Additionally, demonstrating the effectiveness of ourprostate tumor imaging probes in vivo and safety in animal models will serve as initial steps for the subsequent development of a radiotherapeutic agent for clinical use. The PIs will test the central hypothesis and accomplish the overall objective of thisapplication by pursuing the following specific aims: Phase I 1) optimize the nucleophilic 18F labeling of CTT-54; 2) chemical/biochemical evaluation of lead compounds from AIM 1. Phase II Aims: 1) In vivo evaluation of selected PET tracers produced by Phase I and In vivo testing of lead compound for safety and pharmacokinetics Milestones include: labeling of CTT-54 with 1) an overall yield of 40%, high specific activity (gt500 Ci/mmole), stability of gt90% for up to 6 hours, 2) targeting of prostate cancerin mouse xenograft model and 3) a safety profile that will support filing an IND. The proposed work is expected to yield the following outcomes. First, a labeling chemistry that can be used in any one of the 277 PET centers in the United States. Secondly,a safety profile of the labeled lead compound that would support an investigation new drug application with the FDA. The high- affinity small-molecule targeting platform upon which our lead compound is based is unique compared to other targeting moleculesbecause it has demonstrated irreversible binding to the prostate tumor biomarker PSMA. These unique characteristics make this compound is a more attractive targeting platform for prostate tumor binding with enhanced translational potential. It is expectedthat the proposed work will result in optimized prostate cancer imaging agents, which is important because better detection agents are essential for assisting clinicians in staging prostate cancer, developing personalized therapy, and monitoring treatment. PUBLIC HEALTH RELEVANCE: The overall goal of this application is to develop a novel clinically relevant diagnostic for prostate cancer that capitalizes on the potency and specific affinity of small-molecule inhibitors to PSMA. The overall objectives of this application are to further the development our primary PSMA inhibitor, CTT-54 by optimizing the 18F-labeling chemistry, demonstrating PET imaging of prostate cancer in animal models systems, and initiate toxicology studies in support of clinicaltrials. The preliminary data presented demonstrates that a small molecule inhibitor of PSMA can target and image prostate cancer when coupled to a radionuclide tracer.

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