SCH66336 (Sarasar®), an oral farnesyl transferase inhibitor, synergizes with temozolomide and radiation therapy for orthotopic malignant gliomas

Proc Amer Assoc Cancer Res, Volume 47, 2006 3798 Background: Malignant gliomas are highly lethal tumors that display resistance to current therapies. The best treatment modality currently available for these tumors is a combination of maximal surgical resection followed by radiation therapy and concurrent temozolomide, an oral alkylating imidazotetrazine derivative. Although this combination has demonstrated activity, development of resistance and disease progression is common. Thus, additional agents to augment the effectiveness of this approach are needed. The presence of increased Ras signaling in malignant glioma offers a potential novel target. We now report the in vitro and orthotopic in vivo results of combination therapy using irradiation, temozolomide and [SCH66336][1], an oral farnesyl transferase inhibitors, in a murine model of glioblastoma multiforme (GBM). Methods: To examine the activity of radiation, temozolomide, and [SCH66336][1] U87 in vitro and in U87-induced intracranial tumors in SCID or nude mice were evaluated following treatment combinations. Experimental regimens included vehicle control, radiation and temozolomide (2.5Gy/day for 2 days, 5mg/kg/day 90 min prior to radiation), or [SCH66336][1] (80 mg/kg [SCH66336][1] by oral gavage once daily) alone and in combination with [SCH66336][1]. Endpoints evaluated included cell number, proliferation index, apoptotic index, and Ras activation. After completion of the experiment (defined as control or treated animals with symptomatic disease), animals were evaluated by MRI (T1, T2, T1 + gadolinium), sacrificed, and the brains perfused. Sections (5um) including tumor and adjacent brain were prepared and stained for CD31, Ki67 and an apoptotic marker. Results: As previously reported, radiation and concurrent temozolomide can induce significant cellular damage as demonstrated by proliferation inhibition and apoptosis. Similarly, [SCH66336][1] independently inhibited Ras pathway signaling as determined by the activity of Ras isotypes and activation of downstream targets. [SCH66336][1] alone had limited ability to inhibit orthotopic U87 tumors (T/C of 0.67), while the combination of radiation and temozolomide produced significant inhibition (T/C of 0.42). With concurrent [SCH66336][1], radiation, and temozolomide, a decrease in T/C of 0.02 was observed with the majority of animals demonstrating a decrease in tumor volume (p <0.04). Discussion: The addition of [SCH66336][1] to radiation and temozolomide increases the level of apoptosis in vitro and tumor response in vivo in an orthotopic GBM model. Further analysis of the tumor microenvironment of treated animals in long-term studies is now ongoing. The data above provides support for the initiation of a clinical trial in adult and pediatric patients with newly diagnosed high-grade gliomas where [SCH66336][1] is added concurrently with radiation and temozolomide. [1]: /lookup/external-ref?link_type=GENPEPT&access_num=SCH66336&atom=%2Fcanres%2F66%2F8_Supplement%2F893.3.atom