Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial

Evolving studies with several different targeted therapeutic agents are demonstrating that patients with genomic alterations of the target, including amplification, translocation and mutation, are more likely to respond to the therapy. Recent studies indicate that numerous components of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway are targeted by amplification, mutation and translocation more frequently than any other pathway in cancer patients, with resultant activation of the pathway. This warrants exploiting the PI3K/AKT pathway for cancer drug discovery.

http://www.dipbsf.uninsubria.it/monti/BFPN%202009/nrd1902.pdf

Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery

Purpose Renal cell carcinoma (RCC) is characterized by loss of von Hippel Lindau tumor suppressor gene activity, resulting in high expression of pro-angiogenic growth factors: vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). SU11248 (sunitinib malate), a small molecule inhibitor with high binding affinity for VEGF and PDGF receptors, was tested for clinical activity in patients with metastatic RCC. Patients and Methods Patients with metastatic RCC and progression on first-line cytokine therapy were enrolled onto a multicenter phase II trial. SU11248 monotherapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off. Overall response rate was the primary end point, and time to progression and safety were secondary end points. Results Twenty-five (40%) of 63 patients treated with SU11248 achieved partial responses; 17 additional patients (27%) demonstrated stable disease lasting ≥ 3 months. Median time to progression in the 6...

Activity of SU11248, a Multitargeted Inhibitor of Vascular Endothelial Growth Factor Receptor and Platelet-Derived Growth Factor Receptor, in Patients With Metastatic Renal Cell Carcinoma

Molecular imaging, which can allow the non-invasive monitoring of biological processes in living subjects, has the potential to enhance understanding of disease and drug activity in both preclinical and clinical drug studies, aiding effective translational research. Gambhir and colleagues review the applications of molecular imaging in drug development, and discuss challenges that need to be addressed to optimize its utility.

Molecular imaging in drug development

Phosphatidylinositol 3-kinase (PI3K) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling pathway play an important role in multiple cellular functions such as cell metabolism, proliferation, cell-cycle progression, and survival. PI3K is activated by growth factors and angiogenesis inducers such as vascular endothelial growth factor (VEGF) and angiopoietins. The amplification and mutations of PI3K and the loss of the tumor suppressor PTEN are common in various kinds of human solid tumors. The genetic alterations of upstream and downstream of PI3K signaling molecules such as receptor tyrosine kinases and AKT, respectively, are also frequently altered in human cancer. PI3K signaling regulates tumor growth and angiogenesis by activating AKT and other targets, and by inducing HIF-1 and VEGF expression. Angiogenesis is required for tumor growth and metastasis. In this review, we highlight the recent studies on the roles and mechanisms of PI3K and PTEN in regulating tumorigenesis and angiogenesis, and the roles of the downstream targets of PI3K for transmitting the signals. We also discuss the crosstalk of these signaling molecules and cellular events during tumor growth, metastasis, and tumor angiogenesis. Finally, we summarize the potential applications of PI3K, AKT, and mTOR inhibitors and their outcome in clinical trials for cancer treatment.

PI3K/PTEN signaling in angiogenesis and tumorigenesis

Receptor tyrosine kinase activation contributes to cell viability during cytotoxic therapy. The novel broad spectrum receptor tyrosine kinase inhibitor, SU11248, inhibits vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor, c-kit, and fetal liver tyrosine kinase 3. In this study, we maintained SU11248 plasma levels beyond the completion of radiotherapy to determine whether tumor regrowth can be delayed. The antiangiogenic effects of SU11248 were demonstrated using human umbilical vein endothelial cells in vitro. Apoptosis increased and clonogenic survival decreased when SU11248 was used in combination with radiation from 0 to 6 Gy on endothelial cells. In vivo tumor growth delay was increased in C57B6J mice with Lewis lung carcinoma or glioblastoma multiform (GL261) hind limb tumors. Mice were treated with daily i.p. injections (40 mg/kg) of SU11248 during 7 days of radiation treatment (21 Gy). Combined treatment with SU11248 and radiation significantly reduced tumor volume as compared with either treatment alone. Concomitant reduction in vasculature was confirmed using the dorsal vascular window model. The vascular length established using images taken from a consistent quadrant in the window show the combination therapy was more effective in destroying tumor vasculature than either treatment alone. SU11248 maintenance administration beyond the completion of radiotherapy results in prolongation of tumor control. In summary, SU11248 enhances radiation-induced endothelial cytotoxicity, resulting in tumor vascular destruction and tumor control when combined with fractionated radiotherapy in murine tumor models. Moreover, inhibition of angiogenesis well beyond radiation therapy may be a promising treatment paradigm for refractory human neoplasms.

https://cancerres.aacrjournals.org/content/canres/63/14/4009.full.pdf

SU11248 Maintenance Therapy Prevents Tumor Regrowth after Fractionated Irradiation of Murine Tumor Models

The phosphatidylinositol 3′-kinase (PI3k)/protein kinase B (PKB/Akt) signal transduction pathway plays a critical role in mediating endothelial cell survival and function during oxidative stress. The role of the PI3k/Akt signaling pathway in promoting cell viability was studied in vascular endothelial cells treated with ionizing radiation. Western blot analysis showed that Akt was rapidly phosphorylated in response to radiation in primary culture endothelial cells (human umbilical vascular endothelial cells) in the absence of serum or growth factors. PI3k consists of p85 and p110 subunits, which play a central upstream role in Akt activation in response to exogenous stimuli. The δ isoform of the p110 subunit is expressed in endothelial cells. We studied the effects of the p110δ specific inhibitor IC486068, which abrogated radiation-induced phosphorylation of Akt. IC486068 enhanced radiation-induced apoptosis in endothelial cells and reduced cell migration and tubule formation of endothelial cells in Matrigel following irradiation. In vivo tumor growth delay was studied in mice with Lewis lung carcinoma and GL261 hind limb tumors. Mice were treated with daily i.p. injections (25 mg/kg) of IC486068 during 6 days of radiation treatment (18 Gy). Combined treatment with IC486068 and radiation significantly reduced tumor volume as compared with either treatment alone. Reduction in vasculature was confirmed using the dorsal skinfold vascular window model. The vascular length density was measured by use of the tumor vascular window model and showed IC486068 significantly enhanced radiation-induced destruction of tumor vasculature as compared with either treatment alone. IC486068 enhances radiation-induced endothelial cytotoxicity, resulting in tumor vascular destruction and tumor control when combined with fractionated radiotherapy in murine tumor models. These findings suggest that p110δ is a therapeutic target to enhance radiation-induced tumor control.

https://cancerres.aacrjournals.org/content/canres/64/14/4893.full.pdf

A Specific Antagonist of the p110δ Catalytic Component of Phosphatidylinositol 3′-Kinase, IC486068, Enhances Radiation-Induced Tumor Vascular Destruction

Erratum: A specific antagonist of the p110δ catalytic component of phosphatidylinositol 3′-kinase, IC486068, enhances radiation-induced tumor vascular destruction (Cancer Research (July 2004) 64 (4893-4899)

PURPOSE To evaluate the diagnostic accuracy of power Doppler sonography for the depiction of changes in tumor vascularity with various therapeutic regimens. MATERIALS AND METHODS Tumor cells were implanted subcutaneously in thirty-two mice and assigned to four treatment groups: control, radiation therapy, antiangiogenesis therapy (VEGF [vascular endothelial growth factor] receptor antagonist, SU11248), or combined antiangiogenesis and radiation therapy. Twenty of these mice were scanned with power Doppler sonography at two time points over the course of treatment, and power-weighted pixel densities were assessed. The other twelve mice each underwent subcutaneous placement of a dorsal skin-fold window over the tumor site, allowing for daily angiogenesis assessment of vascular length density. All tumor specimens had correlative histologic analyses performed, including immunohistochemical stains for microvasculature. RESULTS Sonographic measurements revealed significant longitudinal differences in tumor vascularity among the four treatment groups: control mice receiving no treatment demonstrated a doubling in intra-tumor color pixel density (P < 0.02); those receiving radiation alone increased by 68% (P < 0.04); those receiving oral therapy alone increased by 44% (P = 0.016); and those receiving combination therapy decreased by 38% (P < 0.02). Tumor vascularity independently measured in the twelve mice with the skin-fold windows revealed a similar response to each type of treatment. Post-mortem tumor histology was consistent with both sonographic and skin-fold window measurements. CONCLUSION Power Doppler sonography was accurate and reliable in measuring tumor vascularity changes in this model. These results were independently confirmed by a quantitative method relying on direct visualization of the microvasculature. Because it is rapid and non-invasive, sonographic quantification is beneficial in assessing the anti-angiogenic effects of various treatment strategies for cancer.

Aaron J. Schueneman

Papers

SU11248 Maintenance Therapy Prevents Tumor Regrowth after Fractionated Irradiation of Murine Tumor Models

A Specific Antagonist of the p110δ Catalytic Component of Phosphatidylinositol 3′-Kinase, IC486068, Enhances Radiation-Induced Tumor Vascular Destruction

Erratum: A specific antagonist of the p110δ catalytic component of phosphatidylinositol 3′-kinase, IC486068, enhances radiation-induced tumor vascular destruction (Cancer Research (July 2004) 64 (4893-4899)

Sonographic depiction of changes of tumor vascularity in response to various therapies.