Review
Recent advances in targeted therapy for glioblastoma Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nyu Medical Center on 07/01/15 For personal use only.
Expert Rev. Neurother. Early online, 1–12 (2015)
Shivani Mittal, Shrikant Pradhan and Tapasya Srivastava* South Campus, Delhi University, Department of Genetics, New Delhi, India *Author for correspondence: [email protected]
Glioblastomas are the most common form of brain tumor with a very dismal prognosis. While a standard treatment regimen of surgery followed by chemo/radiotherapy is currently used, this has only marginally improved the survival time of patients with little benefit on tumor recurrence. Although many molecular targets have already been identified and tested in clinical trials, very few are approved for use in clinics. Efforts are ongoing to target newer molecules that could be used for drug development. This review provides up-to-date information on the drugs and their molecular targets, which are currently in different stages of clinical trials. Since multiple signaling pathways are deregulated, it appears that the use of combination drugs along with personalized targeting approach would provide better therapy in the future. KEYWORDS: clinical trials . epidermal growth factor receptor . glioblastomas . glioma stem cells . platelet-derived growth factor receptor family . tyrosine kinase inhibitors family
Glioblastomas (GBMs), a group of highly heterogeneous tumors, are the most common neoplasms of the brain. Treatment of these highly aggressive tumors has been quite challenging, with recurrence as a major issue. The standard treatment protocol for GBM is surgical removal of the tumor, followed by radio/ chemotherapy. The median survival time for newly diagnosed GBM patients with the current treatment regime is only 13–16 months and the progression-free survival (PFS) time is 5–8 months [1], with 53.9% as 6 months PFS and 26.9% as 2 years overall survival (OS) rates. The patients with recurrent disease have the worst prognosis with a median survival time of 3–9 months [2]. Very few drugs have been approved by the US FDA for treating GBM patients: carmustine, lomustine, temozolomide (TMZ) and bevacizumab. However, only TMZ has emerged as the drug of choice in clinical practices. Since several genetic lesions are involved in the pathogenesis of this deadly disease, there is a need to target multiple molecules. Preclinical studies have shown that targeting core pathways associated with GBMs (like receptor tyrosine kinases, Ras, PI3K, p53 and retinoblastoma signaling networks) have the potential to develop into meaningful therapeutic strategies. The current focus of the basic and
informahealthcare.com
10.1586/14737175.2015.1061934
.
temozolomide . vascular endothelial growth factor receptor
translational research is, therefore, to discover novel key targets and develop therapeutic molecules against them, which can then be used in combination with the current treatment. Here, we provide a comprehensive review on some such molecules, and those from associated networks, which are currently in different phases of clinical trials, either alone or in combination. Alkylating chemotherapy
Three of the most commonly used alkylating agents in chemotherapy: TMZ, carmustine and lomustine, are discussed below. Temozolomide
TMZ (Temodal/Temodar), an alkylating agent, has been demonstrated to be a safe and effective adjuvant for GBM treatment. This oral drug gets rapidly absorbed, easily crosses the blood–brain barrier (BBB) and induces apoptosis of tumor cells by generating a wide spectrum of methyl adducts, thus damaging the DNA mismatch repair cycle [3]. In a significant Phase III trial published in 2005, involving 573 patients with a median age of 56 years, radiation therapy (RT) alone was compared with RT plus concurrent TMZ in patients with GBMs. The latter treatment resulted in an increased survival from 12.1 to
2015 Informa UK Ltd
ISSN 1473-7175
1
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nyu Medical Center on 07/01/15 For personal use only.
Review
Mittal, Pradhan & Srivastava
14.6 months and the 2-year OS also increased to 26.5% as compared with 10.4% in case of RT alone. By the end of 5 years of the study, 85% of patients had completed treatment as planned and the remaining discontinued due to toxic effects, including neutropenia and thrombocytopenia. A significant improvement of 9.8% survival rates was observed as compared with 1.9% in RT-alone treatment [1]. The standard of care followed for newly diagnosed GBM patients is concurrent TMZ (75 mg/m2/day for
Recent advances in targeted therapy for glioblastoma Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nyu Medical Center on 07/01/15 For personal use only.
Expert Rev. Neurother. Early online, 1–12 (2015)
Shivani Mittal, Shrikant Pradhan and Tapasya Srivastava* South Campus, Delhi University, Department of Genetics, New Delhi, India *Author for correspondence: [email protected]
Glioblastomas are the most common form of brain tumor with a very dismal prognosis. While a standard treatment regimen of surgery followed by chemo/radiotherapy is currently used, this has only marginally improved the survival time of patients with little benefit on tumor recurrence. Although many molecular targets have already been identified and tested in clinical trials, very few are approved for use in clinics. Efforts are ongoing to target newer molecules that could be used for drug development. This review provides up-to-date information on the drugs and their molecular targets, which are currently in different stages of clinical trials. Since multiple signaling pathways are deregulated, it appears that the use of combination drugs along with personalized targeting approach would provide better therapy in the future. KEYWORDS: clinical trials . epidermal growth factor receptor . glioblastomas . glioma stem cells . platelet-derived growth factor receptor family . tyrosine kinase inhibitors family
Glioblastomas (GBMs), a group of highly heterogeneous tumors, are the most common neoplasms of the brain. Treatment of these highly aggressive tumors has been quite challenging, with recurrence as a major issue. The standard treatment protocol for GBM is surgical removal of the tumor, followed by radio/ chemotherapy. The median survival time for newly diagnosed GBM patients with the current treatment regime is only 13–16 months and the progression-free survival (PFS) time is 5–8 months [1], with 53.9% as 6 months PFS and 26.9% as 2 years overall survival (OS) rates. The patients with recurrent disease have the worst prognosis with a median survival time of 3–9 months [2]. Very few drugs have been approved by the US FDA for treating GBM patients: carmustine, lomustine, temozolomide (TMZ) and bevacizumab. However, only TMZ has emerged as the drug of choice in clinical practices. Since several genetic lesions are involved in the pathogenesis of this deadly disease, there is a need to target multiple molecules. Preclinical studies have shown that targeting core pathways associated with GBMs (like receptor tyrosine kinases, Ras, PI3K, p53 and retinoblastoma signaling networks) have the potential to develop into meaningful therapeutic strategies. The current focus of the basic and
informahealthcare.com
10.1586/14737175.2015.1061934
.
temozolomide . vascular endothelial growth factor receptor
translational research is, therefore, to discover novel key targets and develop therapeutic molecules against them, which can then be used in combination with the current treatment. Here, we provide a comprehensive review on some such molecules, and those from associated networks, which are currently in different phases of clinical trials, either alone or in combination. Alkylating chemotherapy
Three of the most commonly used alkylating agents in chemotherapy: TMZ, carmustine and lomustine, are discussed below. Temozolomide
TMZ (Temodal/Temodar), an alkylating agent, has been demonstrated to be a safe and effective adjuvant for GBM treatment. This oral drug gets rapidly absorbed, easily crosses the blood–brain barrier (BBB) and induces apoptosis of tumor cells by generating a wide spectrum of methyl adducts, thus damaging the DNA mismatch repair cycle [3]. In a significant Phase III trial published in 2005, involving 573 patients with a median age of 56 years, radiation therapy (RT) alone was compared with RT plus concurrent TMZ in patients with GBMs. The latter treatment resulted in an increased survival from 12.1 to
2015 Informa UK Ltd
ISSN 1473-7175
1
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Nyu Medical Center on 07/01/15 For personal use only.
Review
Mittal, Pradhan & Srivastava
14.6 months and the 2-year OS also increased to 26.5% as compared with 10.4% in case of RT alone. By the end of 5 years of the study, 85% of patients had completed treatment as planned and the remaining discontinued due to toxic effects, including neutropenia and thrombocytopenia. A significant improvement of 9.8% survival rates was observed as compared with 1.9% in RT-alone treatment [1]. The standard of care followed for newly diagnosed GBM patients is concurrent TMZ (75 mg/m2/day for
