Brent R. Stockwell, Ph.D. is an Associate Professor of Biological Sciences and of Chemistry at Columbia University, an Early Career Scientist of the Howard Hughes Medical Institute and author of The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines, which was called “critical reading” by Robert Bazell, chief science correspondent at NBC News and “an absolute page-turner” that manages to “distill a complex, changing field into a beautifully written, well-crafted story” by Siddhartha Mukherjee, winner of the 2011 Pulitzer Prize for General Nonfiction.
Dr. Stockwell’s research involves the discovery of small molecules that can be used to understand and treat cancer and neurodegeneration. He has received numerous awards, including a Burroughs Wellcome Fund Career Award at the Scientific Interface, and a Beckman Young Investigator Award. He has published 59 scientific papers, is an inventor on 10 issued US patents, has given 60 invited presentations around the world, and has received 33 research grants for over $10 million. He co-founded the biopharmaceutical companies CombinatoRx (now Zalicus) and Solaris Therapeutics. You can follow him on Twitter at @bstockwell.
A few years back, a 75-year-old woman whom we will call Dorothy went to see her doctor and received a disturbing diagnosis: Dorothy had developed chronic lymphocytic leukemia (CLL), a type of cancer of the white blood cells. Hearing the words diagnosis and cancer together in the same sentence in your doctor’s office will likely induce a sense of fear and panic, before any mitigating factors seep into your consciousness. This fear alone may jeopardize your well-being, as has been remarked upon in a recent Soapbox Science blogpost by David Ropeik.
Dorothy was at the beginning of her disease course. Each patient’s cancer can be assigned a specific stage in its evolution from a single ill-behaved cell to a massive metastatic invader1. Dorothy was fortunate, if such a word is appropriate in this context, to have stage 0 CLL, which indicates merely an unusually large number of lymphocytes (white blood cells), but no other, more dangerous, manifestations of disease. Since cancers are better treated at early stages, this appeared to be good news, in a relative sense. Unlike more aggressive and rapidly fatal cancers such as pancreatic cancer, the clinical course of CLL is uncertain. One patient may live with the disease for decades without treatment, whereas others will rapidly develop a more advanced disease and need aggressive drug therapy, which may or may not be effective2. So, although Dorothy faced an uncertain future, all indications were that she should be optimistic.
Two years passed as Dorothy watched her leukemia, and in this time, it evolved to stage 1 CLL, manifesting as enlarged lymph nodes. Nine moths later, Dorothy’s health problems began to mount. She endured deep-vein thrombosis, a clotting of her veins, which caused a blockage in one of her arteries in her lungs. Three months later, in April of 2010, Dorothy came down with a weeklong fever and cough, and developed swelling of her legs and a general weariness, for which she was admitted to Montreal General Hospital3. Within days, Dorothy’s liver failed, and her mental health declined, as she faded from consciousness into a delirious state. Finally, 48 days after she was admitted to the hospital, and three years from her initial diagnosis, Dorothy succumbed to her disease.
With our burgeoning knowledge of cancer genetics and mechanisms, why is there no drug that could have slowed or reversed the course of Dorothy’s leukemia—is there any hope for the CLL patients of the future? An emerging trend in cancer therapeutics is the need for precise matching of drugs to disease subtypes—could one make a drug that is designed to address the unique networks and proteins found in CLL tumor cells? Such a tailor-made drug for CLL would likely have fewer side effects than the systemic, blunt chemotherapy this is commonly used to treat most cancers today. Moreover, such a customized drug would likely be more effective, by disabling the specific molecular defects found in CLL. This customization of drugs to diseases is an emerging challenge in cancer drug discovery, and indeed in all of medicine—how do we turn our increasingly sophisticated understanding of disease mechanisms into better therapies for patients?
Increasingly in this post-genomic era, our molecular understanding of disease leads us to a protein that appears to be an ideal candidate for attack with a drug. However, more often than not, these therapeutically and biologically attractive proteins are considered undruggable, resistant to modulation with small molecule drugs (most drug molecules are considered small compared to proteins, which are quite large on the scale of atoms).
Orally available drugs typically function by penetrating inside cells and tissues and directly attaching themselves to crucial proteins that regulate or cause disease. However, proteins vary tremendously in their susceptibility to drug-based attacks. A few proteins have large cavities or pockets that are perfectly suited to tightly enveloping small molecule drugs, whereas most proteins have relatively smooth and featureless surfaces, akin to the side of a sheer cliff, with no footholds for drug molecules. Indeed, all known drugs affect just 2% of human proteins, and most of the remaining proteins are considered challenging or impossible to target with small molecule drugs. Unfortunately, most disease-regulating and disease-causing proteins lie within this more challenging category of potential drug targets, suggesting it may not be possible to address the diseases controlled by these proteins.
The Bcl-2 family of proteins has been thought to represent such a class of challenging drug targets, because they function by interacting with other proteins, as most challenging proteins do. That is, their molecular function is to engage in a tight-fitting interaction across a large region of their surface with other proteins—a surface area much larger than a traditional drug molecule can cover. A grand challenge for chemists and biochemists is to create methods for disrupting these large protein-protein interactions. If it were possible to disrupt any protein-protein interaction of interest, potently and specifically, a wealth of new medicines would be within reach; these would likely be far more effective than out current drugs, and they could be targeted to each disease subtype to reduce systemic side effects, such as hair loss and nausea, that are so common with older, blunter drugs.
One approach that is emerging as effective for attacking protein-protein interactions with small molecules is fragment-based drug design. In this approach, pioneered by Stephen Fesik4, instead of throwing thousands of randomly chosen drug candidates at a target protein to find one that sticks, researchers break drug candidates down into smaller functional units, and test these fragments, as they are known, for their ability to interact with a specific protein. Fesik and his colleagues used this approach to design a molecule, piece by piece, that can specifically and potently interact with the Bcl-2 family of proteins that prevent apoptosis, a specific form of cell death that many tumor cells become resistant to5.
This approach appears to have born fruit: in December of 2011, it was reported in the Journal of Clinical Oncology that patients with CLL were particularly susceptible to treatment with the Fesik drug that targets the Bcl-2 family of proteins6. Bcl-2 family proteins play a pivotal and specific role in allowing CLL tumor cells to survive, as though their default state is death. In these specific tumor cells, Bcl-2 proteins serve as a critical switch that turns off their death program; blocking the Bcl-2 proteins with a small molecule drug can re-activate this death program.
This Bcl-2 targeted drug represents new hope for CLL patients, such as Dorothy. However, the implications are even broader: an otherwise challenging set of proteins (Bcl-2 family proteins) has succumbed to a small molecule drug attack. There are more than 20,000 protein-coding human genes, and only 2% of these have been targeted with small molecule drugs. Perhaps we are seeing the beginning of the assault on the remaining proteins, untouched by drugs until now. If fragment-based screening and other emerging methods for tackling these difficult proteins are successful, we may see a renaissance in the coming decade in the fields of drug discovery and medicine.
1. NCI. Stages of Chronic Lymphocytic Leukemia. National Cancer Institute; [cited 1/18/2005]; Available from: http://www.cancer.gov/cancertopics/pdq/treatment/CLL/Patient/page2.
2. Gribben JG, O’Brien S. Update on therapy of chronic lymphocytic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(5):544-50.
3. Esfahani K, Gold P, Wakil S, Michel RP, Solymoss S. Acute liver failure because of chronic lymphocytic leukemia: case report and review of the literature. Curr Oncol. 2011;18(1):39-42. PMCID: 3031356.
4. Shuker SB, Hajduk PJ, Meadows RP, Fesik SW. Discovering high-affinity ligands for proteins: SAR by NMR. Science. 1996;274(5292):1531-4.
5. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435(7042):677-81.
6. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R. Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011.