GW786034 in Patients With Non Small Cell Lung Cancer 3rd Line

Better therapies for patients with NSCLC (Non Small Cell Lung Cancer) who progress after initial chemotherapy is urgently needed. Besides VEGF (vascular endothelial growth factor), human lung cancers are known to express PDGFR (platelet-derived growth factor receptors). NSCLC, like most cancers, involves defects in signal transduction pathways. Receptor tyrosine kinases (RTKs) play a pivotal role in these signaling pathways, transmitting extracellular molecular signals into the cytoplasm and/or nucleus of a cell. Among such RTKs are the receptors for polypeptide growth factors such as epidermal growth factor (EGF), insulin, platelet-derived growth factor (PDGF), neurotrophins (i.e., NGF), and fibroblast growth factor (FGF). Phosphorylation of such RTKs activates their cytoplasmic domain kinase function, which in turns activates downstream signaling molecules. Thus, RTKs are key mediators of cellular signaling as well as oncogenesis resulting from over-expression and activation of such RTKs and their substrates. Due to their pivotal role in normal and aberrant signaling, RTKs are the subject of increasing focus as potential drug targets for the treatment of certain types of cancer. For example, Herceptin.RTM., an inhibitor of HER2/neu, is currently an approved therapy for a certain subset of breast cancer. Iressa.TM. (ZD1839) and Tarceva.TM. (OSI-774), both small-molecule inhibitors of EGFR, have been approved for the treatment of NSCLC. Platelet-derived growth factor (PDGF) and its receptors (PDGFRs) are a family of RTKs that play an important role in the regulation of normal cell growth and differentiation. PDGFRs are involved in a variety of pathological processes, including atherosclerosis, neoplasia, tissue repair, and inflammation. PDGFRs, which consist of two isoforms (alpha and beta), are membrane protein-tyrosine kinases that, upon binding to PDGF, become activated and, via recruitment of SH domain-containing effector molecules, initiate distinct or overlapping signaling cascades that coordinate cellular responses. Expression of a constitutively active PDGFR leads to cellular transformation and suggests that, in normal cells, PDGFR activity must be tightly regulated to oppose continuous activation of its downstream effectors. PDGFR beta, for example, is known to be over-expressed in a large number of tumors, and PDGF treatment causes transformation and malignant tumors in a variety of experimental systems. One study reported the apparent expression of PDGFR alpha in nearly 100% of human lung cancer tumors examined, and reported the growth inhibition of a lung cancer cell line, A549, by Gleevec, an effect that was surmised to be mediated via PDGFR inhibition. Donnem et al evaluated 335 resected patients with stage I to III with NSCLC. Using IHC (immunohistochemical staining) the expression of PDGF-A, -B, -C and -D along with PDGFR alpha and beta. In multivariant analysis high tumor cell expression of PDGF-B and PDGF- alpha were independent negative prognostic predictors. They suggested that PDGF inhibition may be an option for treatment of NSCLC. Socinski et al recently described the activity of sunitnib malate (SU11248) an oral, multitargeted tyrosine kinase inhibitor targeting VEGFR, PDGFR, KIT, FLT3 and RET on tumor cells, tumor neovasculature and pericytes. In an open-label, two-stage, multicenter phase II trial evaluating the single-agent activity of sunitinib in refractory NSCLC, patients with confirmed diagnosis of NSCLC, ECOG PS 0-1, no recent gross hemoptysis, no brain metastases, patients (pts) previously treated with 1-2 chemotherapy regimens, and adequate end-organ function, pts received sunitinib at 50 mg/day po for 4 weeks (wks) followed by 2 wks off treatment (6 wks considered a cycle). A total of 64 pts were enrolled and 63 pts treated. Six confirmed partial responses have been observed among 63 treated patients. Stable disease has been observed in an additional 12 pts (19.0% of all treated patients). Based on this study, Sunitinib appeared to have single-agent activity in previously treated pts with recurrent and advanced NSCLC, with the level of activity similar to currently approved agents. Sunitinib was well tolerated in this population. The trial was extended to explore a continuous dosing strategy of sunitinib at 37.5 mg/day po. In addition to VEGF and PDGFR, expression of c-kit has been described in NSCLC. Moreover, it has been found to have an effect on survival. Micke et al, stained the tumor tissue of 95 consecutive patients with adenocarcinoma of the lung, using a polyclonal c-kit antibody. c-kit expression was correlated with relevant clinical parameters obtained by chart review. Positive c-kit expression in tumor tissue was observed in 61 of 95 patients (64%). Univariate analysis showed a significant effect of T (p = 0.003), N (p = 0.001) and M stage (p \< 0.001) as well as of performance status (p = 0.001), surgical resection (p \< 0.001), and LDH serum levels (p = 0.016) on survival. In contrast, c-kit protein expression was non- significant (p = 0.913). However, multivariate Cox regression with the influential parameters revealed a significant effect of c-kit expression on survival. They concluded that, the receptor tyrosine kinase c-kit is frequently expressed in adenocarcinomas of the lung and has a relevant effect on patient survival. They also concluded that the results of this study support clinical trials targeting the c-kit receptor with specific c-kit inhibitors. Combined blockade of VEGF, PDGFR and c-kit may result in better outcomes for patients with Non Small Cell Lung Carcinoma. Pazopanib is a novel, orally active small molecule inhibitor targeting multiple tyrosine kinases including VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha and - beta, and c-kit. An antitumor effect due to inhibiting of the VEGF driven angiogenic pathway is well established. In addition to its effects on VEGF receptors, pazopanib targets additional tyrosine kinases including PDGF receptors and c-kit that have established roles in tumorigenesis and oncogenic mutations in both have been described. Preliminary data from a phase I study of pazopanib in patients with solid tumors demonstrated early evidence of antitumor activity. Among 43 patients enrolled, a minimal response occurred in 4 patients and stable disease \>6 months, was observed in an additional 6 patients. Pazopanib was well tolerated at doses up to 2000 mg daily. Pazopanib is a potent and selective, orally available, small molecule inhibitor of VEGFR-1, -2, and -3, PDGF-α, PDGF-β, and c-kit tyrosine kinases (TKs). The agent selectively inhibits proliferation of endothelial cells stimulated with VEGF but not with basic fibroblast growth factor. In non-clinical angiogenesis models, pazopanib inhibited VEGF-dependent angiogenesis in a dose-dependent manner and in xenograft tumor models, twice-daily administration of pazopanib significantly inhibited tumor growth in mice implanted with various human tumor cells. Upon chronic oral dosing, pazopanib is expected to inhibit VEGF driven angiogenesis and as a consequence, limit solid tumor growth. Because angiogenesis is necessary for the growth and metastasis of solid tumors, and VEGF is believed to have a pivotal role in this process, pazopanib treatment may have broad-spectrum clinical utility. Based on its ability to target multiple tyrosine kinases including VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha and beta and c-kit, which have been implicated in non small cancer, investigation of Pazopanib in patients with non small cell lung cancer is warranted.