Advances in Molecular Therapies in Patients With Brain Tumors

Advances in Molecular Therapies in Patients With Brain Tumors

from Cancer Control: Journal of the Moffitt Cancer Center

Matrix Metalloproteinase Inhibitors

The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade some components of the extracellular matrix. The human MMP gene family is grouped into five classes by primary structure and substrate specificity (Table 2). A review on MMPs and the development of MMP inhibitors (MMPIs) can be found elsewhere.[137] MMPs degrade the basement membrane and the extracellular matrix, thus facilitating tumor growth, invasion, and spread. The expression of MMP is increased in most cancers, including gliomas. Of all known MMPIs in clinical development (Table 2), marimastat, metastat, and prinomastat have been or are being tested in trials against gliomas.Marimastat

Drug Overview[137-142]. Marimastat (BB-251) is a low molecular weight drug that chelates the Zn++ ion at the active site of MMPs. It is 20% to 50% bioavailable after oral administration, with a linear pharmacokinetics and a Cmax of 1.5 to 3.0 hours. The half-life of marimastat is 8 to 10 hours, so the drug can be given twice a day.[141] The main side effect is a dose-related polyarthritis manifested by arthralgias in large and small joints, sometimes with visible redness and swelling. Marimastat-related arthralgias are treated with nonsteroidal anti-inflammatory drugs and a 10% reduction of the previous dose until symptoms are mild enough to tolerate or disappear.

Clinical Trials. Two phase II trials of marimastat and temozolomide for recurrent GBM and anaplastic gliomas showed that this combination appears to be effective to increase PFS.[143,144] In both trials, patients had progression after surgery, radiation therapy, and one, at most, previous treatment with chemotherapy. Patients received temozolomide at 150 to 200 mg/m2 per day on days 1 to 5 and marimastat at 50 mg orally once a day on days 8 to 28. In the GBM study, 5 patients (11%) had severe arthralgias that prompted drug withdrawal. Seventeen patients in the group with anaplastic gliomas required dose reduction from toxicity, but none were withdrawn. At 6 months, PFS was 39% and 54% for recurrent GBM and anaplastic gliomas, respectively. These figures represent a gain of 29% and 14% over the expected target PFS for recurrent GBM and anaplastic gliomas treated with temozolomide alone.Metastat

Drug Overview[137,140]. Metastat (CMT-3, COL-3, Collagenex) is a chemically modified tetracycline with potent inhibition of MMP-2 and MMP-9 in cancer cell lines. This drug has been tolerated in doses up to 70 mg/m2 per day, with a prolonged half-life and steady-state levels above the concentrations required for in vitro activity.

Clinical Trials. NABTT 9809 is a phase I/II trial to evaluate safety and tolerability of COL-3 in recurrent high-grade gliomas, with escalating doses of 25 mg/m2 up to a maximum dose of 100 mg/m2 once a day for 28 days.[145] Patients with or without EIAEDs are included. The maximum dose has been well tolerated with no responses among 25 patients enrolled thus far.Prinomastat

Drug Overview[140,146-149]. Prinomastat (AG3340), a nonpeptidic MMPI, inhibits MMP-2, -3, -9, and -13 with an IC50 value of 0.1 ng/mL. Its cytostatic activity was optimized by drug fractionation but not by total daily dose, AUC, or Cmax.Prinomastat inhibited tumor growth and induced apoptosis of U87 glioblastoma cell xenografts.[146] The drug is lipophilic and crosses the blood-brain barrier, which prompted the use of prinomastat in clinical trials against glioma. Prinomastat is also synergistic with carboplatin and paclitaxel in vitro.[137] The drug has been tested in doses ranging from 2 to 100 mg orally twice a day.

Clinical Trials. DM99-254 was a randomized, placebo-controlled phase II trial of prinomastat with temozolomide after radiation therapy in patients with newly diagnosed GBM.[150] Patients were randomized after surgery and radiation therapy to continuous prinomastat 25 mg orally twice a day or placebo, plus temozolomide at 200 mg/m2 orally once a day on days 1 to 5 every 28 days. This trial showed that prinomastat added to temozolomide compared with temozolomide alone did not improve 1-year survival rate (44% vs 58%) or PFS (4.5 vs 6 months). The main side effects related to prinomastat were myalgias and arthralgias with swelling in 55% of patients compared with 20% of patients receiving placebo.[150]

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