Cancer Res Treat.  2012 Mar;44(1):1-10.

Present Status and Problems on Molecular Targeted Therapy of Cancer

• Saijo N

Abstract

Numerous clinical trials of molecular targeted drugs for cancer have been conducted, with remarkable results for certain drugs and accumulation of "negative data" causing a hitch in the development plan for some other compounds. Five recent issues and problems of molecular targeted therapies were discussed critically. Drug discovery and effects against driver mutations (activating mutations) and problems: possibility for circumventing inherent and acquired resistance with the aim of achieving radical cure. Synthetic lethality: reasonable patient selection in individualized treatment strategy. Response rate and progression-free survival improvement with or without overall survival benefit and enhancement of toxicity in bevacizumab therapy: best endpoints for the evaluation of effect of antiangiogenic therapy. Negative data on small-molecule targeted therapy, primarily vascular endothelial growth factor tyrosine kinase inhibitors: loose GO or NO-GO decision criteria for further development of new compounds in early clinical trials. Effect of immunotherapy: difficulty to verify by proof of principle study. We are faced to many questions for the development of efficient personalized therapy. Accumulation of scientific global preclinical and clinical evidences is essential to use these new therapeutic modalities for the improvement of oncologic health care.

Keyword

Molecular targeted therapy; Driver mutation; Synthetic letharity; Antiangiogenic therapy; Endpoint determination; Personalised therapy; Resistance

MeSH Terms

Bevacizumab
Antibodies, Monoclonal, Humanized
Delivery of Health Care
Disease-Free Survival
Drug Discovery
Endpoint Determination
Humans
Molecular Targeted Therapy
Patient Selection
Protein-Tyrosine Kinases
Social Change
Vascular Endothelial Growth Factor A
Antibodies, Monoclonal, Humanized
Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor A

Figure

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  Fig. 1 Your Health-CTV Med News Express (From CTV News, Vemurafenib in melanoma: was its phase 3 trial unethical?, with permission from CTV Television Network) [5].

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  Fig. 2 Mechanism for synthetic lethality in BRCA1/2 deficient cancer. Poly ADR-ribose polymerase (PARP) inhibition produces tumor-selective synthetic lethaity. When PARP action is inhibited, SS are converted to DSB at replication. In cells with functional HR pathway, the DSB will be repaired. In cells with a dysfunctional HR pathway, as is the case with BRCA 1 and 2, the lesions go unrepaired and cell death ensues [18,19,21]. BRCA, breast cancer susceptibility gene; DSB, double-strand break; HR, homologous recombination; SSB, single-strand break.

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  Fig. 3 Efficacy of iniparib in triple negative breast cancer progression-free survival/overall survival (phase II study). CI, confidence interval [23].

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  Fig. 4 Schematic illustration of overlap among triple negative breast cancer, basal-like, and BRCA1-related tumors adapted from Pal et al. [25]. BRCA1, breast cancer susceptibility gene.

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  Fig. 5 Increased treatment cost by bevacizumab (Bev). CBDCA, carboplatin; PTL, paclitaxel.

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  Fig. 6 Mode of action of ipilimumab. CTLA-4, cytotoxic T-lymphocyte antigen-4; TCR, T-cell receptor; MHC, major histocompatibility complex; APC, antigen-presenting cell.

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