November 2011

'Developing' drugs

If only it were that easy 

 

Meetings_drugsIn the context of the early embryo or a growing child, the term “development” implies a set of stereotyped transitions from one well-defined stage to another until adulthood is achieved. In this context, the term “drug development” is an oxymoron, as most drug-discovery projects never reach maturity. This is especially true for complex diseases such as cancer, as the diversity of disease mechanisms can make development of effective therapies challenging. Despite these hurdles, exciting progress is being made. In this symposium, we explore some recent advances in the development of cancer therapies. The sessions will discuss the full developmental spectrum of drug-discovery projects -- from new technologies for target discovery to compounds making their ways into the clinic.

Killing cancer cells 

The first session, “Drug Development and Apoptosis: Linking Tumor Regression to Cell Death,” will feature Junying Yuan (Harvard Medical School), who will describe recent work in developing small-molecule inhibitors targeting autophagy, an important catabolic mechanism that mediates the turnover of misfolded proteins and damaged intracellular organelles. The inhibitors have revealed an important tumor-suppressor mechanism that is regulated by autophagy and the possibility of inhibiting autophagy to treat cancer.

The BCL-2 family of apoptotic proteins regulates the critical balance between cellular life and death. Loren Walensky (Dana Farber Cancer Institute) will discuss his laboratory’s progress in dissecting the BCL-2 family interaction network using a novel pharmacological strategy, stabilized alpha-Helices of BCL-2 domains. 

Vishva Dixit (Genentech) will discuss the state of drug development in apoptosis with a focus on IAP and BCL-2 inhibitors. He also will discuss recent progress on the molecular basis of necrosis. While the players that mediate apoptosis are well defined, little is known about what mediates necrosis, except for the recent dramatic discovery of the involvement of the RIP3 kinase.

Targeting each person’s cancer 

The molecular heterogeneity of cancer poses great challenges for drug development, yet it also affords new opportunities for developing highly targeted therapies. In the second session, “Targeted Cancer Drug Development: Defining Molecular Profiles of Sensitivity,” Alan Ashworth (Institute of Cancer Research) will discuss harnessing genetic dependencies in cancer therapy. Many tumours harbour defects in their ability to maintain genomic integrity. His lab used a synthetic lethal approach to target the defect in DNA repair by homologous recombination in tumours with a BRCA1 or BRCA2 mutation. This strategy using PARP inhibitors is showing considerable promise in the clinic. Here, he will describe the approach as well as recent work defining determinants of sensitivity and resistance to PARP inhibitors.

Neal Rosen (Memorial Sloan-Kettering Cancer Center) will discuss molecularly targeted therapies for cancer. Among these targets, the Raf kinase is activated by mutation in several tumors, and inhibitors of B-Raf show great promise in treatment of tumors that harbor activating mutations, such as melanoma. However, in tumors with wild-type Raf genes, the effects of Raf inhibitors are complex, as they perturb feedback mechanisms in the MAP kinase pathway and can induce proliferative responses. Explaining these results requires careful molecular analysis of the dynamic behavior of the pathway in tumor models, which will be the topic of the presentation.

It has been known for many years that metabolism is perturbed in cancer cells. Recently, mutations in components of metabolic pathways have been identified that provide exciting new opportunities for drug development. Scott Biller (Agios Pharmaceuticals) will discuss how metabolism informs cancer drug discovery.

Finding new molecules and targets 

Many exciting new technologies are being developed to identify new drug targets for cancer and other diseases. In the third session, “New Methodologies for Target Discovery and Target Validation,” William Hahn (Dana-Farber Cancer Institute) will discuss how functional genomic approaches now enable the interrogation of gene function at scale and how the integration of functional approaches with other high-throughput technologies permits the identification and validation of cancer targets.

Cancers can show a high degree of cellular heterogenity within tumors. Peter Jackson (Genentech) will discuss proteomic network building to discover new disease genes and drug targets.

Finally, the ubiquitin-proteasome system represents an exciting new opportunity for drug development, as inhibitors of the proteasome are in the clinic. Randall King (Harvard Medical School) will discuss the use of phenotypic screening to discover new inhibitors of ubiquitin ligases and their potential role as novel antimitotic agents.

Meetings_Drug_Dev_KingMeetings_Drug_Dev_Jackson

Randall King (randy_king@hms.harvard.edu) is an associate professor at Harvard Medical School, and Peter K. Jackson (pjackson@gene.com) is director of cell regulation at Genentech Inc.  


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