Publications by authors named "Thea Kalebic"

Background: Antibody-drug conjugates (ADCs) are an emerging technology consisting of an antibody, linker, and toxic agent, which have the potential to offer a targeted therapeutic approach. A novel target recently explored for the treatment of pancreatic cancer is guanylyl cyclase C (GCC). The objective of this study was to determine the anti-tumorigenic activity of TAK-264, an investigational ADC consisting of an antibody targeting GCC linked to a monomethyl auristatin E payload a peptide linker.

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Background: The transmembrane receptor guanylate cyclase-C (GCC) has been found to be expressed in colorectal cancers. However, limited data are available on GCC protein expression in non-colorectal gastrointestinal tumors and few studies have reported whether GCC protein expression was consistently preserved in synchronous primary and metastatic cancer tissues.

Methods: GCC protein status was assessed by immunohistochemistry in tumor specimens from individuals (n = 627) with gastrointestinal tumors, including esophageal (n = 130), gastric (n = 276), pancreatic (n = 136), and colorectal (n = 85) primary and metastatic tumors.

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Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity.

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Purpose: This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC).

Materials And Methods: Adult patients with advanced GI malignancies expressing GCC (H-score ≥ 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264.

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Background The first-in-class antibody-drug conjugate TAK-264 (formerly MLN0264) consists of an antibody targeting guanylyl cyclase C (GCC) conjugated to monomethyl auristatin E (MMAE) via a peptide linker. This phase II study evaluated the efficacy and safety of TAK-264 in patients with adenocarcinoma of the stomach or gastroesophageal junction expressing GCC, who had progressed on ≥1 line of prior therapy. Methods This study used a two-stage design, with an interim analysis conducted after stage I to determine whether to continue to stage II or discontinue on the grounds of futility.

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Antibody-directed cancer chemotherapy in the form of antibody-drug conjugates (ADCs) may improve the therapeutic index with the potential to enhance efficacy and decrease systemic toxicity. ADCs consist of three key components including an antibody that specifically binds to the target, a toxic agent and a linker which releases the toxic agent inside tumor cells. A novel ADC, MLN0264 (TAK-264) was recently investigated in patients with gastrointestinal (GI) malignancies.

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Purpose: To assess the safety, tolerability, and preliminary antitumor activity of the investigational anti-guanylyl cyclase C (GCC) antibody-drug conjugate TAK-264 (formerly MLN0264) in adult patients with advanced gastrointestinal malignancies.

Experimental Design: Adult patients with GCC-expressing gastrointestinal malignancies (H-score ≥ 10) were eligible for inclusion. TAK-264 was administered as a 30-minute intravenous infusion once every 3 weeks for up to 17 cycles.

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Purpose: Ixazomib is an investigational proteasome inhibitor with demonstrated antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and solid tumors. This open-label, phase 1 study investigated intravenous (IV) ixazomib, in adult patients with advanced non-hematologic malignancies.

Methods: Patients received IV ixazomib twice-weekly for up to twelve 21-day cycles.

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We prove that the SH2-containing tyrosine phosphatase 1 (SHP-1) plays a prominent role as resistance determinant of imatinib (IMA) treatment response in chronic myelogenous leukemia cell lines (sensitive/KCL22-S and resistant/KCL22-R). Indeed, SHP-1 expression is significantly lower in resistant than in sensitive cell line, in which coimmunoprecipitation analysis shows the interaction between SHP-1 and a second tyrosine phosphatase SHP-2, a positive regulator of RAS/MAPK pathway. In KCL22-R SHP-1 ectopic expression restores both SHP-1/SHP-2 interaction and IMA responsiveness; it also decreases SHP-2 activity after IMA treatment.

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Resistance to chemotherapeutic agents remains one of the major impediments to a successful treatment of chronic myeloid leukemia (CML). Misregulation of the activity of a specific group of ATP-binding cassette transporters (ABC) is responsible for reducing the intracellular concentration of drugs in leukemic cells. Moreover, a consistent body of evidence also suggests that ABC transporters play a role in cancer progression beyond the efflux of cytotoxic drugs.

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Purpose: Phase I-II studies indicate that imatinib is active in glioblastoma multiforme. To better understand the molecular and clinical effects of imatinib in glioblastoma multiforme, we conducted a neoadjuvant study of imatinib with pretreatment and posttreatment biopsies.

Experimental Design: Patients underwent a computerized tomography-guided biopsy of their brain tumors.

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Purpose: Bone metastases (BM) in non-small-cell lung cancer (NSCLC) may be detected at diagnosis or during the course of the disease, and are associated with a worse prognosis. Currently, there are no predictive or diagnostic markers to identify high-risk patients for metastatic bone dissemination.

Patients And Methods: Thirty patients with resected NSCLC who subsequently developed BM were matched for clinicopathologic parameters to 30 control patients with resected NSCLC without any metastases and 26 patients with resected NSCLC and non-BM lesions.

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Therapeutic approaches aimed at developing epigenetically-effective drugs are under intense investigation. Several classes of enzymes regulating histone acetylation and DNA methylation, which are required for epigenetic transitions, offer attractive targets for therapeutic interventions. Imbalances in histone acetylation and DNA methylation may play a significant role in the development of cancer and leukaemia and may provide a mechanistic rationale for targeting epigenetic modifications.

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The refractoriness of advanced lung cancer to current treatment modalities requires new approaches to reduce the public health burden associated with this disease. One strategy that is currently being tested is chemoprevention, which aims to prevent the development of cancer in populations that are at high risk for cancer due to a variety of genetic or environmental factors. The key to the success of this approach, however, requires the identification of appropriately targeted efficacious, non-toxic agents as well as the methodologies to efficiently test them.

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Recent advances in human genome research have resulted in novel approaches for the identification of epigenetic modifications associated with cancer. Modulators of DNA methylation and chromatin structure have a dramatic effect on gene expression, cellular proliferation, differentiation, and apoptosis. Molecular pathways regulating epigenetic events that occur during tumorigenesis have been exploited as new targets for therapeutic intervention.

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