Where is the Future of Drug Discovery for Cancer?

With both small molecules and biologics succeeding in trials and in the clinic, the scope of drug discovery in cancer is changing. We asked a group of researchers to share their visions for how to identify new targets and how to approach taming them. Cancer Metabolism Games Giulio Superti-Furga Research Center for Molecular Medicine of the Austrian Academy of Sciences We have known for a long time that cancer cells adopt metabolic states that fit their growth impetus and reflect their relinquishing of tissue homeostasis, yet the degree and variety of ways by which metabolic networks are rewired in tumors continues to surprise us. What has received less attention is the interplay between the metabolism of tumors and other cells in the microenvironment. Metabolism is not cellautonomous; instead, it reflects an obligatory dialog between tumor cells and the surrounding tissue. We are increasingly appreciating that immune cells are also profoundly affected by metabolism, including nutrient, metal, and oxygen levels. These insights highlight a potential innovative therapeutic target: the integrated metabolic space of tumor, stromal, and immune cells, where cells must compete for nutrients or enter mutually advantageous dependencies. An opportunity now exists to alter nutrient traffic to draw in and activate the right immune cell types and to disadvantage cancer cells. But how to attempt this? The solute carrier and ABC membrane transporters are responsible for influx and efflux of nutrients and metabolites. These transporters are differentially expressed in different cell types and respond to environmental supply and internal demand. They are also exquisitely druggable. By targeting transporters, perhaps in combination, we may be able to subtly and safely turn the tables in the cancer metabolism game in favor of immune cell well-being and cancer cell starvation for the re-establishment of healthy tissue homeostasis. Designer Proteins as Cancer Therapeutics Jennifer Cochran Stanford University Monoclonal antibodies dominate the modern pharmaceutical industry. These agents have achieved clinical success, led by recent excitement about arming them with chemotherapeutic agents for targeted drug delivery or interactions with the immune system. Despite these advances, challenges in the field remain, including how to best tackle tumor and patient heterogeneity, rapid drug resistance, and issues with effective tumor penetration and delivery across the blood-brain barrier. Advances in our understanding of disease pathophysiology and the development of rational and combinatorial technologies for creating protein-based biologics are spawning drug candidates with improved therapeutic and safety profiles. We now have ‘‘multi-specific’’ proteins that target and modulate several key biochemical pathways and ‘‘multi-epitopic’’ proteins that bind different locations of the same target for improved efficacy. Researchers are also exploring peptides and so-called ‘‘alternative scaffolds’’ that are modular like antibodies, but evoke potential benefits such as enhanced tumor penetration. Along with these elegant approaches come development, manufacturing, or regulatory hurdles, but also new opportunities for impactful cancer treatments. Clinical trials are increasingly combining targeted therapies or coupling them with more traditional modalities such as chemotherapy or radiation to address multiple facets of cancer. While these approaches bring increased costs and questions about toxicity, they are proving highly effective and are poised to offer new standards of care. Growing the Drug Target Space Craig M. Crews Yale University Greater than 20% of industrial cancer drug development programs focus on just eight proteins—sadly ironic in this post-genomic era, when
20,000 possible proteins are known. While many potential drug targets are enzymes, it is clear that non-enzymatic proteins also play key roles in cancer biology. Currently, these structural and regulatory classes of proteins appear ‘‘undruggable,’’ since they lack a catalytic site for small-molecule inhibition. This unsuitability is especially applicable to transcription factors, which regulate gene expression via protein complex formation. Given these challenges, how can one make these proteins pharmaceutically vulnerable? RNAi and CRISPR offer some hope via preventing oncogene expression. However, their clinical potential has not been fully realized due to challenges with cost, delivery, and off-target effects. Clearly, new approaches are needed to identify modulators of protein expression (and thereby, function). Ideally, these approaches should be small molecule based, should possess favorable pharmaceutical properties, and should have the potential to target all proteins, irrespective of protein class. One emerging approach to target the ‘‘undruggable’’ proteome is the use of small molecule proteolysis targeting chimera (PROTACs) to induce the deliberate degradation of specific proteins by the ubiquitin/proteasome system. By co-opting the normal cellular quality control machinery responsible for removing unwanted proteins, all classes of proteins could be controlled using small molecules, greatly expanding the number of ‘‘druggable’’ protein targets.