Combination strategies with PARP inhibitors in BRCA-mutated triple-negative breast cancer: overcoming resistance mechanisms.

Triple-negative breast cancer (TNBC) is a particularly aggressive breast cancer subtype, characterised by a higher incidence in younger women, rapid metastasis, and a generally poor prognosis. Patients with TNBC and BRCA mutations face additional therapeutic challenges due to the cancer's intrinsic resistance to conventional therapies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have emerged as a promising targeted treatment for BRCA-mutated TNBC, exploiting vulnerabilities in the homologous recombination repair (HRR) pathway.

A phase I trial to determine safety and pharmacokinetics of ASLAN002, an oral MET superfamily kinase inhibitor, in patients with advanced or metastatic solid cancers.

Background The MET tyrosine kinase and its ligand, hepatocyte growth factor (HGF) also known as scatter factor, are associated with tumourigenesis and metastasis by promotion of scattering, proliferation, angiogenesis, motility and invasion. ASLAN-002 is a potent inhibitor of MET as well as related kinases. A phase I dose escalation study was conducted to determine the safety and pharmacokinetics of ASLAN-002 in patients with advanced cancer.

Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors.

Background: ZD6126 is a novel vascular-targeting agent that disrupts the endothelial tubulin cytoskeleton causing selective occlusion of tumor vasculature and extensive tumor necrosis. This Phase I clinical study was conducted to evaluate the dose and administration schedule of ZD6126.

Methods: Adult patients with solid tumors refractory to existing treatments received a 10-min, single-dose intravenous infusion of ZD6126 every 14 or 21 days.

Antiangiogenic and antitumor activity of a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor ZD6474 in a metastatic human pancreatic tumor model.

ZD6474 is a novel, orally available inhibitor of vascular endothelial growth factor receptor kinase insert domain receptor/flk-1 tyrosine kinase activity with additional activity against the epidermal growth factor receptor-1 tyrosine kinase. The aim of this study was to evaluate ZD6474, alone and in combination with gemcitabine, in an orthotopic model of metastatic pancreatic cancer. Nude mice (nine to 10/group) were injected orthotopically with 1x10(6) L3.

Improving the design of phase II trials of cytostatic anticancer agents.

This paper examines the design of phase II trials in oncology and recommends departing from the traditional uncontrolled trial design. Entrance into phase II clinical evaluation represents a key milestone in the development of any new cancer therapy. As novel molecular-targeted therapies are introduced, whose primary action is to slow the growth of tumors, it will be important to ensure that the clinical trial design will effectively capture any clinical benefit of these agents.

Optimizing randomized phase II trials assessing tumor progression.

The traditional development paradigm for phase II trials in oncology has been challenged in recent years by the introduction of cytostatic therapies. These agents slow the growth of tumors rather than cause high rates of shrinkage, this argues for the use of endpoints that measure growth inhibition such as progression free survival. We have previously argued the need for randomized trials in this setting.

Vascular targeting in pancreatic cancer: the novel tubulin-binding agent ZD6126 reveals antitumor activity in primary and metastatic tumor models.

ZD6126 is a novel vascular-targeting agent that acts by disrupting the tubulin cytoskeleton of an immature tumor endothelium, leading to an occlusion of tumor blood vessels and a subsequent tumor necrosis. We wanted to evaluate ZD6126 in primary and metastatic tumor models of human pancreatic cancer. Nude mice were injected orthotopically with L3.

A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer.

Purpose: To determine the efficacy and safety of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase with additional activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously treated metastatic breast cancer.

Patients And Methods: Eligible patients had histologically confirmed metastatic breast cancer and had received prior treatment with an anthracycline and taxane; measurable disease was required. Patients were enrolled sequentially into one of two dose cohorts, 100 or 300 mg orally once daily; 28 days defined one cycle.

Inhibition of SRC tyrosine kinase as treatment for human pancreatic cancer growing orthotopically in nude mice.

Purpose: The Src family comprises a family of nonreceptor intracellular tyrosine kinases that mediate a variety of cellular pathways. Src kinases are overexpressed in a variety of human tumors, including cancer of the colon, breast, and pancreas, and they are an integral part of tumor cell signaling pathways associated with migration, proliferation, adhesion, and angiogenesis.

Experimental Design: We investigated whether the blockade of Src kinase by daily oral administration of the novel Src tyrosine kinase inhibitor AZM475271 [kindly provided by AstraZeneca (Macclesfield, United Kingdom)], alone or in combination with intraperitoneal gemcitabine, can inhibit growth and metastasis of orthotopically implanted human pancreatic carcinoma cells in nude mice.