Julia Glade-Bender

VEGF blocking therapy in the treatment of cancer

It is widely accepted that tumour growth beyond a few cubic millimetres cannot occur without the induction of a new vascular supply. Inhibiting the development of new blood vessels (antiangiogenesis) is a potential approach to cancer therapy that has attracted interest in recent years. In theory, this approach should be relatively selective for tumour cells. The endothelial cells which form new vascular networks in tumours are responding to angiogenic stimuli produced by the tumour, but are themselves genetically normal. Endothelium in normal tissue, by contrast, is usually quiescent. Vascular endothelial growth factor (VEGF) is the best-characterised pro-angiogenic factor. It is virtually ubiquitous in human tumours, and higher levels have been correlated with more aggressive disease. Effective blockade of the VEGF pathway has been demonstrated with multiple agents: neutralising antibody, receptor tyrosine kinase inhibitors, and ribozyme or antisense molecules targeting expression. Promising preclinical data document the potential of these agents for tumour growth inhibition and even tumour regression, yet translation of novel therapeutics targeting the VEGF pathway to the clinic has proved a substantial challenge in itself. While showing clear evidence of antitumour activity over a broad spectrum of experimental tumours, the proper selection, dose, timing and sequence of anti-VEGF treatment in human cancer is not at all obvious. Classic Phase I dose escalation trial design may need to be modified, as higher doses may not be optimal in all patients or for all tumours. In addition, alternate or secondary biological end points (e.g., non-progression) may be needed for early phase studies to document true activity, so as not to abandon effective agents. Recent studies of the neutralising antibody bevacizumab, and small molecule tyrosine kinase inhibitor SU5416, demonstrate that, while unlikely to be effective as monotherapy, incorporation of VEGF blockade into cytotoxic regimens may increase overall response rates. However, incorporation may also produce new toxicities, including thromboembolic complications and bleeding. Newer oral agents, such as SU6668, SU11248, PTK787/ZK222584 and ZD6474, are particularly interesting for their potential for chronic therapy. Future clinical trials are likely to build on past experience with stricter entry criteria, supportive care guidelines and the use of surrogate markers.

Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia (TACL) consortium.

Outcomes remain poor for children after relapse of acute lymphoblastic leukemia (ALL), especially after early marrow relapse. Bortezomib is a proteasome inhibitor with in vitro synergy with corticosteroids and clinical activity in human lymphoid malignancies.

Phase I and Pharmacokinetic Study of Sunitinib in Pediatric Patients with Refractory Solid Tumors: A Children's Oncology Group Study

Purpose: Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor. The purpose of this study was to determine the recommended phase 2 dose, pharmacokinetics, pharmacodynamic effects, and preliminary antitumor activity of sunitinib in a pediatric population. Experimental Design: Patients who were 2 to 21 years of age with refractory solid tumors were eligible if they had measurable or evaluable disease and met baseline organ function requirements. Patients received sunitinib once daily for 28 days followed by a 14-day break between each cycle. Dose levels of 15 and 20 mg/m2/d were evaluated, with dose escalation based on a 3 + 3 design. Sunitinib pharmacokinetics and biomarkers of angiogenesis were also evaluated during the first cycle. Results: Twenty-three patients were treated (median age 13.9 years; range, 3.9–20.6 years). The most common toxicities were neutropenia, thrombocytopenia, elevated liver transaminases, gastrointestinal symptoms, and fatigue. Two patients developed dose-limiting reductions in cardiac ejection fraction prompting a protocol amendment to exclude patients with previous exposure to anthracyclines or cardiac radiation. In patients without these cardiac risk factors, the maximum tolerated dose (MTD) was 15 mg/m2/d. Steady-state plasma concentrations were reached by day 7. No objective responses were observed. Four patients with sarcoma and glioma had stable disease for 2 to 9 cycles. Conclusions: Cardiac toxicity precluded determination of a recommended dose for pediatric patients with previous anthracycline or cardiac radiation exposure. The MTD of sunitinib for patients without risk factors for cardiac toxicity is 15 mg/m2/d for 28 days followed by a 14-day break. Clin Cancer Res; 17(15); 5113–22. ©2011 AACR.

Neuropsychological functioning of children treated with intensive chemotherapy followed by myeloablative consolidation chemotherapy and autologous hematopoietic cell rescue for newly diagnosed CNS tumors: An analysis of the Head Start II survivors

To evaluate the neuropsychological late effects amongst survivors treated on the Head Start II protocol between 1997 and 2003.

Angiogenesis and Vascular Targeting in Ewing Sarcoma: A Review of Preclinical and Clinical Data

Ewing sarcoma is the second most common type of bone cancer in children and young adults. In recent years, the mechanisms by which these tumors develop and maintain their vascular supply have been elucidated. Additional work has demonstrated that inhibition of angiogenic pathways or disruption of established vasculature can attenuate the growth of Ewing sarcoma mouse xenografts. Early clinical data suggest that these results also may extend to patients with Ewing sarcoma who are treated with antiangiogenic or antivascular therapies. For the current review, the authors summarized the available data supporting this approach. Cancer 2010.

Recurrent EML4–NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy

Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6–NTRK3 gene fusion. However, a number of case reports have identified variant fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4–NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6–NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4–NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4–NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4–NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.

Growth plate abnormalities in pediatric cancer patients undergoing phase 1 anti‐angiogenic therapy: A report from the children's oncology group phase I consortium

Pre‐clinical studies suggest that anti‐angiogenic agents may be toxic to the developing growth plate. The purpose of this study was to evaluate the incidence of growth plate abnormalities in children with refractory cancer undergoing anti‐angiogenic therapy.

Growth plate abnormalities in pediatric cancer patients undergoing phase 1 anti-angiogenic therapy

Pre‐clinical studies suggest that anti‐angiogenic agents may be toxic to the developing growth plate. The purpose of this study was to evaluate the incidence of growth plate abnormalities in children with refractory cancer undergoing anti‐angiogenic therapy.

Abstract C108: An expanded imaging cohort of pazopanib in children and adolescents with relapsed or refractory soft tissue sarcoma (ADVL0815): A Children's Oncology Group phase I consortium trial.

Background: Pazopanib (NCT00929903) is an orally available small molecule inhibitor of VEGFR 1–3, PDGFR α/β, and c-kit, which has been shown to prolong progression free survival in adults with soft tissue sarcoma (STS). Following a standard phase I dose escalation trial to determine the pediatric maximum tolerated dose (MTD), an expanded cohort of children and adolescents with relapsed and refractory STS and at least one lesion amenable to dynamic contrast enhanced MRI (DCE-MRI) was studied to explore changes in tumor blood volume and vascular permeability following initiation of pazopanib, and to correlate these changes with clinical outcome. Methods: Oral pazopanib was administered at 450mg/m2 once daily in 28 day cycles, for up to 24 cycles. DCE-MRI scans were obtained at baseline and within 15 × 2 days after initiation of pazopanib. DCE-MRI data sets were analyzed using a two compartment kinetic model yielding estimates of fractional blood volume and the permeability transfer constant (Ki). Results: 10 subjects were enrolled [5 male; median age 17 yrs (range, 8–23)], of whom 8 had paired DCE-MRI scans of sufficient quality to be evaluable. Subjects received a median of 4 cycles (range 1–7; 3 remain on study receiving courses 6, 7 and 8). One subject had a dose limiting toxicity of Gr3 back and extremity pain with Gr3 sensory neuropathy. Other non-dose limiting toxicities occurring in >10% of subjects (n=10) during the first cycle included mild myelosuppression, sinus bradycardia, fatigue, diarrhea, nausea, vomiting, anorexia, dehydration, dizziness, headache, liver transaminase elevation and hyperglycemia. All subjects with evaluable DCE-MRI (n=8) experienced a decrease in tumor blood volume following initiation of pazopanib, with a mean pre-treatment level of 16% (range 1–29%) versus 7% (0–15%) post-treatment (p Conclusions: DCE-MRI changes in tumor blood volume and Ki in pediatric and adolescent patients with soft tissue sarcoma are supportive of physiological activity and the antiangiogenic mechanism of pazopanib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C108.