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AbstractBiomarkers that assess the therapeutic response to anticancer treatments may aid in tailoring therapeutic regimens to individuals. Ideally, the relative contributory effect of each agent in a muti-agent regimen can be discerned. Hypoxia is a prevalent feature of solid tumors, associated with treatment failure, poor prognosis, and increased metastasis. TH-302, a hypoxia-activated prodrug of the DNA cross-linker bromo isophosphoramide mustard, has demonstrated broad efficacy in preclinical models and is exhibiting promising activity in multiple ongoing clinical trials, both as a monotherapy and in combination therapy regimens. Three fundamental biomarker platforms were assessed in this preclinical study: positron emission tomography (PET) imaging employing the tracer [18F]-HX4; immunohistochemistry of isolated tumor tissue employing antibodies directed against the exogenous hypoxia biomarker pimonidazole (PIMO) and the endogenous hypoxia biomarker carbonic anhydrase IX (CA-IX); and ELISA-based quantification of circulating plasma CA-IX. Both HX4 and PIMO utilize the same 2-nitroimidazole hypoxia-sensitive trigger for their activity and specificity as TH-302 utilizes. CA-IX is up-regulated by two distinct hypoxia sensing pathways: hypoxia-inducible factor 1; and the unfolded protein response. The human H460 non-small cell lung cancer human tumor ectopic xenograft model was employed for these studies. When the tumor size was 300-600 mm3, a single dose of TH-302 (150 mg/kg, ip) or vehicle was administered. This TH-302 treatment regimen yields a tumor growth inhibition of 58%, TGD1000 of 10 d, and maximum body weight loss of 2%. [18F]-HX4 uptake was assessed by PET/CT imaging and the tumor to muscle ratio (T/M) was determined. Animals were scanned pre- and post-treatment and the T/M ratio was significantly reduced 72 hours after TH-302 treatment (from 3.3 ± 0.3 to 2.1 ± 0.2, p<0.005). A slight increase in T/M was observed in the vehicle-treated animals (3.3 ± 0.4 to 3.6 ± 0.2, p>0.05). Blood was collected from the animals pre- and post- treatment via retro-orbital vein. Plasma CA-IX changed from baseline 165 ± 13 to 104 ± 9.3 pg/ml 72 hours after TH-302 dosing, a 37% reduction (p<0.05; n=10 per group). No change was observed in the vehicle-treated group. For tissue biomarker analysis, tumors were harvested 72 hours after TH-302 treatment, and tumor hypoxia was assessed by semi-quantitative morphometric analysis of the PIMO immunostaining at that time. The hypoxic fraction (HF) was 13 ± 1.7% in the vehicle group (n=5) and 5.8 ± 0.5% in the TH-302 treatment group (n=6, p<0.05). Strong co-localization of CA-IX and PIMO expression was observed in consecutive sections. These preclinical results highlight the promise of using TH-302 response biomarkers tested in the clinical setting for their ability to help guide TH-302 treatment decisions after the initiation of therapy.Citation Format: Jessica D. Sun, Qian Liu, Dharmendra Ahluwalia, Yan Wang, Anna-Katrin Szardenings, Luis F. Gomez, Hartmuth Kolb, Karen A. Pierce, Sheryl Brown-Shimer, Walter A. Carney, Charles P. Hart. Response biomarkers for the hypoxia-targeted drug TH-302: imaging, plasma, and tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5583. doi:10.1158/1538-7445.AM2013-5583

01 Jan 2013·Biomarkers in Cancer

Circulating HER2 Extracellular Domain: A Specific and Quantitative Biomarker of Prognostic Value in all Breast Cancer Patients?

Review

Author: Carney, Walter P. ; Bernhardt, Dirk ; Jasani, Bharat

The HER2 oncoprotein has emerged as an essential biomarker in the treatment of breast cancer patients. Once the primary breast cancer is removed, there is an increasing need to detect breast cancer recurrence as early as possible with the hope that earlier intervention with new anti-HER2 therapies will improve quality of life and increase overall survival. Numerous publications have shown that increasing blood levels of circulating HER2 is an early indicator of progression, particularly in HER2-positive patients and that the rise and fall parallels the clinical course of disease and independent of therapy. Many studies show that the HER2 status of the primary tumor may not fully and accurately reflect the HER2 status of recurrent cancer. Thus, elevated serum HER2 levels may be an early signal of the emergence of a HER2-positive metastatic tumor and therefore alert the physician to re-assess HER2 status using a tissue test.

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Pipeline

Pipeline Snapshot as of 23 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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