But as Stokoe explains, it’s often difficult to find genetic changes that are responsible for the cancer. Most cancers, especially solid tumors, “are just genomic carnage. All hell has broken loose,” he says. “I think the hard part is to try and find the genetic alterations that have actually benefited the tumor cell over all of the noise that has come along for the ride.”
The drug that has kept Hanson out of the “big lab in the sky” illustrates the principles of targeted therapy design. Before he took the drug, Hanson’s B cells were crowding out red blood cells and platelets and enlarging his lymph nodes to the point that his blood circulation was affected. Walking down a hallway became hard work. He sweated at night. With a weakened immune system, he was always worried about getting infections. After the sixth round of chemotherapy, Hanson’s lymphocyte level was 30 times higher than normal.
Because cancerous cells continue to mutate, “the clone you started with is not the clone that kills you,” says Hanson. He eventually experienced the common CLL mutation in which the short arm of chromosome 17, where the gene for p53 resides, was deleted. His B cells were free of the tumor suppressor. “That’s a true death sentence,” he says. The life expectancy for patients with that mutation is, on average, up to a year.
That’s when Hanson heard of a clinical trial at the Arthur G. James Cancer Hospital at the Ohio State University Comprehensive Cancer Center that was being run by John Byrd and his colleagues. The trial was testing a drug developed by Pharmacyclics that binds to a molecule called Bruton’s tyrosine kinase, or Btk for short. Hanson was allowed to enroll in the trial during its early phases.
Joseph Buggy at Pharmacyclics describes how the company knew to go after Btk. There was 10 years of scientific literature supporting the importance of the B-cell receptor signaling pathway in B-cell proliferation. Btk is an essential kinase in the signaling pathway downstream of the B-cell receptor. The pathway in which Btk is involved leads to the phosphorylation of several proteins that are antiapoptotic. When phosphorylated, these proteins prevent apoptosis.
But the most critical piece of information about Btk was genetic. There is a disease called X-linked agammaglobulinemia in which patients lack mature B cells. “That told us that if we could come up with a molecule that was selective enough for Btk, it shouldn’t affect other organs or tissues,” says Buggy.
Every expert interviewed for this article emphasized that genetic validation is the key to finding proper targets. Genetic validation “takes guesswork and the need to understand the biology almost out of it,” says Kevan Shokat at the University of California, San Francisco. “For every degree you get separated from the mutated human oncogene, the more biology is incumbent on you to figure out in order to be sure it’s going to be a satisfactory target.”
Pharmacyclics developed ibrutinib, an irreversible Btk inhibitor that binds to a cysteine found in only 10 or so kinases. When this drug blocks Btk, it induces apoptosis in cells that otherwise refuse to die (1). The irreversible binding of ibrutinib to the kinase meant that “you can durably inhibit the target, even if the drug is eliminated quickly” from the body when it’s not bound to the enzyme, says Buggy. Once bound, ibrutinib molecules cling onto Btk for as long as 24 hours. The drug is now going onto phase III clinical trials.