Drugging the "Undruggable" MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers.

Effective treatment of pediatric solid tumors has been hampered by the predominance of currently "undruggable" driver transcription factors. Improving outcomes while decreasing the toxicity of treatment necessitates the development of novel agents that can directly inhibit or degrade these elusive targets. MYCN in pediatric neural-derived tumors, including neuroblastoma and medulloblastoma, is a paradigmatic example of this problem. Attempts to directly and specifically target MYCN have failed due to its similarity to MYC, the unstructured nature of MYC family proteins in their monomeric form, the lack of an understanding of MYCN-interacting proteins and ability to test their relevance in vivo, the inability to obtain structural information on MYCN protein complexes, and the challenges of using traditional small molecules to inhibit protein-protein or protein-DNA interactions. However, there is now promise for directly targeting MYCN based on scientific and technological advances on all of these fronts. Here, we discuss prior challenges and the reasons for renewed optimism in directly targeting this "undruggable" transcription factor, which we hope will lead to improved outcomes for patients with pediatric cancer and create a framework for targeting driver oncoproteins regulating gene transcription.

Phenotypic screening in cancer drug discovery - past, present and future.

There has been a resurgence of interest in the use of phenotypic screens in drug discovery as an alternative to target-focused approaches. Given that oncology is currently the most active therapeutic area, and also one in which target-focused approaches have been particularly prominent in the past two decades, we investigated the contribution of phenotypic assays to oncology drug discovery by analysing the origins of all new small-molecule cancer drugs approved by the US Food and Drug Administration (FDA) over the past 15 years and those currently in clinical development. Although the majority of these drugs originated from target-based discovery, we identified a significant number whose discovery depended on phenotypic screening approaches. We postulate that the contribution of phenotypic screening to cancer drug discovery has been hampered by a reliance on 'classical' nonspecific drug effects such as cytotoxicity and mitotic arrest, exacerbated by a paucity of mechanistically defined cellular models for therapeutically translatable cancer phenotypes. However, technical and biological advances that enable such mechanistically informed phenotypic models have the potential to empower phenotypic drug discovery in oncology.

The NCI60 human tumour cell line anticancer drug screen.

The US National Cancer Institute (NCI) 60 human tumour cell line anticancer drug screen (NCI60) was developed in the late 1980s as an in vitro drug-discovery tool intended to supplant the use of transplantable animal tumours in anticancer drug screening. This screening model was rapidly recognized as a rich source of information about the mechanisms of growth inhibition and tumour-cell kill. Recently, its role has changed to that of a service screen supporting the cancer research community. Here I review the development, use and productivity of the screen, highlighting several outcomes that have contributed to advances in cancer chemotherapy.

Anticancer drug development at the US National Cancer Institute.

Anticancer drug discovery and development is a rapidly evolving field. Recent advances in molecular oncology and the effort to completely sequence the human genome has led to an explosion in our understanding of the mechanisms involved in the transformation and growth of malignant cells. This in turn has led to major changes in our approach to traditional drug discovery and development. A dynamic example of how genomics is affecting cancer developmental therapeutics is provided by the ongoing changes being implemented in the anticancer drug development program run by the US National Cancer Institute (NCI). This review summarizes the history of drug screening and development efforts at the NCI over the past five decades from its inception up to its current state emphasizing molecularly targeted therapies. These changes have not only had an impact on drug discovery, but they are also providing new paradigms for the design and conduct of preclinical and early clinical trials.

Assay-assisted treatment selection for women with breast or ovarian cancer.

Although women suffering from advanced cancer of the breast or ovary are unlikely to be cured, several active agents are available that can prolong their lives. The use of these agents is based on demonstrated benefit in large randomized clinical trials, and the clinical activity of these chemotherapy regimens is initially high, with 60%-70% of patients responding. Unfortunately, their benefit in the second-line setting is often limited, with less than 30% of patients showing significant disease response. Thus some 70% of patients may undergo ineffective treatment during the course of their disease, while still suffering from significant chemotherapy-related toxicity. Having some foreknowledge of a given agent's expected result before its administration would therefore benefit the individual patient. In vitro drug response testing, first developed to assist in the selection of antibiotics for patients with bacterial infections, has recently been demonstrated to accurately predict how cancer patients will respond to chemotherapy. This review discusses the historical development of in vitro testing for cancer patients, some of the pitfalls encountered, and offers an assessment of their current utility. Results of various clinical trials that evaluated correlations between in vitro tumor response and clinical outcomes are described. These data suggest that in vitro drug response assays can accurately predict drug resistance and can identify patients who are more or less likely to benefit from a given agent.

In vitro assay-assisted treatment selection for women with breast or ovarian cancer.

The selection of chemotherapy for women with breast or ovarian carcinoma has been traditionally based on results from phase III comparative trials that define the most active drugs and drug combinations. This approach has led to a significant prolongation of the lives of these patients. Unfortunately, few patients with advanced stage IV disease are cured using the currently available regimens. In order to improve the selection process for individual patients, various types of in vitro tests that assess the activity of standard drugs on a patient's tumor have been developed over the past five decades. As with bacterial culture and sensitivity tests, significant predictive correlations between in vitro drug-response assays and cancer patient response and survival have been demonstrated. Medicare currently covers in vitro drug-resistance assays. This review discusses the historical development of in vitro drug-response assays and the clinical validation of various technologies currently available to assist the clinician in selecting the optimal therapy for each patient.

[History and new development of screening and evaluation methods of anticancer drugs used in vivo and in vitro]. / Historique et récents développements des méthodes de criblage et d'évaluation des molécules anticancéreuses in vitro et in vivo.

Screening methods for the detection of anticancer activity are of crucial importance in order to find solid tumor-specific agents. A review of past screening methods is followed by a description of present methodologies targetted toward the discovery of such agents. Finally, we discuss primary and secondary in vivo evaluation in experimental chemotherapy.