Dataset Information

Combining targeted therapies: practical issues to consider at the bench and bedside.

ABSTRACT: Numerous practical issues must be considered when combining targeted therapies in early clinical drug development. These include tumor resistance mechanisms, the existence of multiple, redundant signaling pathways, and the failure of single-agent therapies to achieve cures. The strategies adopted to examine combinatorial therapy include the goal of hitting more than one target by specifically inhibiting signal transduction cascades and suppressing specific mechanisms of action with the use of multitargeted kinase inhibitors made possible by high-throughput screening techniques, combinatorial chemistry, and chemoinformatics. Two complex considerations are: which agents to combine given the heterogeneity of tumors and their various underlying perturbations, including secondary mutations and feedback loops, and how to translate findings from the bench to the bedside or directly from the bedside. Another consideration is: When is there enough information to provide a rationale for instituting a phase I trial? Various strategies have been used in combining molecules, including targeting diverse pathways, inhibiting upstream and downstream signals, and adopting a synthetic lethality paradigm. Other issues are: determining appropriate target populations for treatment, how to combine therapeutics with diagnostics, and the frequency of targets in patients referred to clinical trials. Here, we review these issues and we propose various novel trial designs that are logical for determining the efficacy of a drug or drug combination for personalized treatment. A difficult issue that must be answered is how many and which drugs to combine. Recent technologies, such as multiplexed assay platforms and bioinformatics, will shape the future of clinical trials and help answer these questions surrounding combinatorial treatment.

SUBMITTER: Rodon J

PROVIDER: S-EPMC3227881 | biostudies-other | 2010

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Combining targeted therapies: practical issues to consider at the bench and bedside.

Rodon Jordi J Perez Jose J Kurzrock Razelle R

The oncologist 20100115 1

Numerous practical issues must be considered when combining targeted therapies in early clinical drug development. These include tumor resistance mechanisms, the existence of multiple, redundant signaling pathways, and the failure of single-agent therapies to achieve cures. The strategies adopted to examine combinatorial therapy include the goal of hitting more than one target by specifically inhibiting signal transduction cascades and suppressing specific mechanisms of action with the use of mu ...[more]

PMID: 20080862

Similar Datasets

Project description:Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the occurrence of vestibular schwannomas (VSs), schwannomas of other cranial, spinal and cutaneous nerves, cranial and spinal meningiomas and/or other central nervous system (CNS) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, retinal hamartomas, dermal schwannomas (i.e., NF2-plaques), and (few) café-au-lait spots. Clinically, NF2 children fall into two main groups: (1) congenital NF2 - with bilateral VSs detected as early as the first days to months of life, which can be stable/asymptomatic for one-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Some individuals can develop unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system [i.e., mosaic NF2] or multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas (histologically proven) [schwannomatosis]. NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by coupled germ-line and mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region and the NF2 gene. Data driven from in vitro and animal studies on the merlin pathway [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed to multiple tumour shrinkage and/or regression and tumour arrest of progression with functional improvement.

Project description:The current standard care of treatment for glioblastoma multiforme (GBM) is never curative and exclusively involves the use of cytoxics upfront (e.g., radiation and chemotherapy). Current clinical protocols involve the use of single-agent targeted therapies, which inhibit specific pathways. Given the functional redundancies present in human tumors and escape mechanisms, it is highly unlikely that such a monotherapy approach will be successful in the treatment of GBM. Future directions of therapy for GBMs will likely involve the use of therapeutic cocktails, including more than one target specific inhibitors based on tumor escape mechanism, genetic, epigenetic and molecular signatures. This review addresses some of the relevant issues.Correlative clinical studies from various clinical trials and preclinical studies have provided the meticulous use of chemotherapeutics and radiation based on molecular profiling of tumors. Alkylating agents such as temozolomide lose their efficacy if DNA repair enzyme expression is upregulated. The alternative strategies include targeting the enzyme or one can use poly (ADP) ribose inhibitor to inhibit base excision repair pathway rather than mismatch repair pathway. Currently, several inhibitors in this category are in clinical trials. Next, we have addressed new avenues including radiosensitizers, hypoxia, metabolism, angiogenesis, invasive and infiltrative nature of tumors and potential molecular targets, which can be exploited for clinical trials. Finally, we have included some aspect of genome-wide association studies and correlative analysis and the lessons learned to design better clinical trials.Advances in profiling the noncoding RNAs, genetic, epigenetic profiles, metabolomics, genomics and proteomics may uncover important resistance mechanisms in GBM. Personalized therapy using various therapeutic cocktails targeting these resistance mechanisms may prove even more effective in the future management of GBMs.

Dataset Information

Combining targeted therapies: practical issues to consider at the bench and bedside.

Publications

Combining targeted therapies: practical issues to consider at the bench and bedside.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets