Another JAK2 Inhibitor Shows Promise against Myelofibrosis
An experimental drug designed to inhibit growth-promoting signals associated with a mutant form of the Janus-activated kinase 2 (JAK2) protein reduced clinical symptoms and led to durable responses in some patients with myelofibrosis , a disorder in which the bone marrow is replaced by fibrous tissue. The phase I dose-escalation study, published online in the Journal of Clinical Oncology on January 10, evaluated a selective JAK2 inhibitor called TG101348.
Fifty-nine patients were enrolled in the trial, including 28 in the dose-escalation phase. A substantial portion of patients experienced improvements in primary symptoms, including enlargement of the spleen. Myelofibrosis disrupts the production of blood cells, which can lead to severe anemia, weakness, fatigue, and frequently an enlarged spleen and liver.
There are no FDA-approved treatments for myelofibrosis, a debilitating chronic myeloproliferative disorder . The disease can arise independently (primary myelofibrosis) or develop late in the course of two more benign myeloproliferative disorders, essential thrombocythemia or polycythemia vera . Currently, patients with myelofibrosis receive palliative treatment meant to ease the symptoms of the disease.
Although TG101348 was generally well tolerated, the drug caused anemia in some patients, especially at higher doses. A follow-up trial is being planned to see whether adjusting the dose will allow patients to achieve the benefits without the anemia. A second planned trial will test the agent in patients with polycythemia vera.
“The take-home message of this study is that selective anti-JAK2 drugs such as TG101348 should be pursued further in polycythemia vera,” said the lead investigator, Dr. Ayalew Tefferi of the Mayo Clinic. Another message, he continued, is that the scientific community should be aware that the anti-JAK2 drugs tested to date are different from each other, in terms of both their therapeutic activity and their side effects. For example, patients at risk of anemia perhaps should consider drugs that do not have this side effect, he said.
In September 2010, researchers reported positive results from a trial testing an experimental agent known as INCB018424 in patients with advanced myelofibrosis. Unlike TG101348, INCB018424 inhibits JAK1 as well as JAK2. The development of JAK2 inhibitors followed the discovery, in 2005, of an activating mutation in the JAK2 gene in 90 percent of patients with polycythemia vera and 60 percent of patients with primary myelofibrosis or essential thrombocythemia.
An accompanying editorial notes that the development of JAK2 inhibitors “has ushered in a new era of targeted therapies” for myeloproliferative disorders that lack the Philadelphia chromosome . Patients usually see improvements in their symptoms within a month of starting therapy, and this improvement appears to be durable, wrote Dr. Srdan Verstovsek of the University of Texas M. D. Anderson Cancer Center. The drugs do not eradicate the malignant clone, however, and more research is needed to learn how best to use them, he added.
Treatment for Ductal Carcinoma In Situ Varies Substantially
Treatment for ductal carcinoma in situ (DCIS), a noninvasive condition that may progress to invasive breast cancer, varies substantially between surgeons, and this variation can affect the likelihood of disease recurrence, researchers reported online January 3 in the Journal of the National Cancer Institute.
The researchers, led by Dr. Andrew Dick from the nonprofit RAND Corporation, studied medical records from 994 women with DCIS who were treated in either Monroe County, NY, or at the Henry Ford Health System in Detroit. They collected data on disease characteristics, such as tumor size and the width of the surgical margins (i.e., the closeness of cancer cells to the edge of the excised tissue); treatments, including surgery, radiation therapy, and tamoxifen ; and outcomes, primarily recurrence in the same breast.
Almost all women had breast-conserving surgery (BCS) as a first procedure, but more than half required at least one additional surgery—BCS or mastectomy —to remove residual cancer cells. Only 60 percent of women who had BCS as their final surgery received radiation therapy, despite evidence from clinical trials showing that adjuvant radiation therapy reduces disease recurrence.
The authors found that recurrence rates were lowest for women who had a mastectomy, highest for women who had BCS without radiation therapy, and intermediate for those who had BCS followed by radiation therapy. Women who had positive or close surgical margins after their last surgery were also more likely to have a recurrence than women whose surgical margins were free of cancer cells.
The authors also found that treatments and surgical margin width varied widely among surgeons, leading to large variations in recurrence risk. The authors estimated that increasing surgeons' rates of radiation therapy use and decreasing the rates of positive or close margins could reduce 5- and 10-year recurrence rates by 15 to 30 percent.
The study could not determine whether these results were influenced by women’s potential preference for surgeons who are known for recommending less invasive treatment, by variation in decision making among surgeons, or by a lack of communication over the risks and benefits of each procedure. However, “because of the importance of treatment choice and margin status in predicting outcomes, these unexplained differences by surgeons could have profound implications for health outcomes,” the authors concluded.
Major Gene Mutation Identified in Lymphoma Tumors
Researchers have identified a recurring genetic mutation that drives the growth of some lymphoma tumors by activating multiple signaling pathways associated with cancer. The mutation, in a gene called MYD88, was found in nearly a third of patients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), which is the least curable form of DLBCL. Further experiments pointed to possible treatment strategies, Dr. Louis Staudt of NCI’s Center for Cancer Research and his colleagues reported December 22 in Nature.
The MYD88 protein normally plays a role in the body’s immune response. But the researchers found that the mutant form of MYD88, known as L265P, spontaneously assembles a protein complex that promotes the survival of lymphoma cells through the NF-κB and JAK-STAT3 signaling pathways. Twenty-nine percent of the 155 ABC DLBCL samples examined had the same MYD88 mutation, and the change was rare or absent in other kinds of DLBCL and other lymphomas.
The researchers also found that blocking a component of the protein complex assembled by the L265P form of MYD88—a protein called IRAK4—caused lymphoma cells with the MYD88 mutation to die. Pharmaceutical companies are developing IRAK4 inhibitors to treat inflammatory and autoimmune diseases, and these agents could be tested in lymphoma, the researchers said.
To make the discovery, the researchers first identified genes that are required for the survival of ABC DLBCL (through a technique known as RNA interference). After identifying MYD88 and IRAK1 (a gene related to IRAK4) as essential genes, the researchers sequenced the genes in patient samples and found the recurring MYD88 mutation. The next step was to understand how the MYD88 mutation contributes to cancer.
“A major part of the story for DLBCL has now been solved,” said Dr. Staudt, noting that the MYD88 mutation is the most common mutation found in DLBCL to date. In effect, lymphoma cells “hijack” an immune regulator pathway for their malignant purposes, he continued. MYD88 may be frequently mutated, he speculated, because the mutation controls two major signaling pathways in cancer and “cancer cells like to get the most bang for their buck.”