Kareem news puts rare cancer in spotlight

November 18, 2009 – 6:29 pm by Michael Christel

As a lifelong Philadelphia 76ers fan, I grew up rooting against Kareem Abdul-Jabbar. After all, the big, bad Lakers were always the one team blocking my beloved Sixers – led by Dr. J and company – from winning the NBA championship until “we� finally broke through in 1983, sweeping L.A. in four games. (Philly hasn’t won the title since, but perhaps that’s a story for another blog for another day).

But I always admired Kareem’s play on the court – his smooth, graceful style that was amazing for a man that stands 7-foot-2 and had arms that could reach up to the nosebleed seats. And, of course, those effortless, rainbow sky hooks that were impossible to defend and always left me – just a kid at the time – muttering, “Does he ever miss that @#$%*&! shot?” He was an underrated rebounder and passer in his heyday as well, and is considered one of the smartest and most cerebral sports stars ever.

That’s why I got a bit nostalgic last week when Abdul-Jabbar, now 62, revealed to the world that he has Philadelphia chromosome-positive chronic myeloid leukemia (CML), a rare type of blood cancer. The basketball legend was diagnosed almost a year ago and decided to go public now to educate people about the disease, once considered a likely death sentence but now very much a manageable cancer with new, albeit costly, oral medications.

“I think it’s possible for someone in my position to help save lives,� Abdul-Jabbar told CNN. Watch the interview here.

CML, a cancer that affects the blood and bone marrow, has a worldwide prevalence of about 200,000 patients. Roughly 5,000 new cases are expected to be diagnosed this year.

Abdul-Jabbar now serves as a spokesman for Novartis, which makes tyrosine kinase inhibitors Gleevec, the top treatment for CML, and Tasigna, usually given to patients who cannot take certain other leukemia medications or have tried to do so unsuccessfully. Gleevec and Tasigna specifically target the abnormal protein known as BCR-ABL, which triggers the onset of CML. Sprycel, a multi-targeted tyrosine kinase inhibitor made by Bristol Myers-Squibb, is another approved drug for the disease.

U.K. funding for Sprycel and Tasgina, both second-line treatments, took a potential hit yesterday when the National Institute for Health and Clinical Excellence (NICE) proposed rejecting their use for CML patients who experience resistance or are intolerant to Gleevec.

The majority of newly diagnosed CML patients initially respond well to tyrosine kinase inhibitor treatments. But, as Abdul-Jabbar even noted last week, not all people with leukemia can benefit from these drugs.

There are some who fail or become intolerant to one or more tyrosine kinase inhibitors. In many of these cases, the cause of failure can be traced to the emergence of BCR-ABL mutations. A common mutation called T315I renders CML resistant to all currently approved tyrosine kinase inhibitors, thus creating a significant unmet medical need in the management of the disease.

So I decided to do a little digging in our database to see what potential new CML therapies are on the horizon. Here’s what I found out:

- Earlier this month, FDA accepted ChemGenex Pharmaceuticals’ new drug application for Omapro for patients with CML who have failed treatment with Gleevec and who have developed the BCR-ABL T315I mutation. The filing, originally submitted in September, has been granted priority review by FDA. Omapro has already received orphan-drug designation in the United States and Europe, and fast-track status from FDA.

Omapro is administered subcutaneously and acts differently from tyrosine kinase inhibitors such as Gleevec. According to ChemGenex, the drug specifically binds to the ribosomal A-site cleft and inhibits protein translation of short-lived oncoproteins that are upregulated in leukemic cells. Preclinical research has demonstrated that Omapro kills human CML stem cells that are known to be insensitive to tyrosine kinase inhibitors.

- In late March, Deciphera Pharmaceuticals LLC launched a Phase I trial for DCC-2036 at MD Anderson Cancer Center in Houston. DCC-2036 is a a BCR-ABL kinase inhibitor based on a proprietary “kinase switch pocket� platform which designs small molecule inhibitors to constrain otherwise activated kinases in inactive conformational states. The approach has particular application in oncology, where kinases become conformationally activated by mutation.

The early trial will evaluate the safety and tolerability of once-a-day continuous oral dosing of DCC-2036 in patients with treatment resistant or intolerant CML or acute lymphoblastic leukemia, including patients with the T315I amino acid mutation. The study will also enroll patients at Tufts Medical Center in Boston.

- AP24534, another tyrosine kinase inhibitor of the BCR-ABL mutation, is presently in Phase I trials under development by Ariad Pharmaceutical Inc. In preclinical studies, AP24534 demonstrated efficacy and oral dosing flexibility in animal models of CML, including forms of the disease caused by clinically relevant variants of BCR-ABL. The drug also inhibited the T315I mutation.

Earlier this month, the journal Cancer Cell published a paper describing for the first time the chemical structure and preclinical characterization of AP24534.

- Bosutinib, a third-generation tyrosine kinase inhibitor developed by Wyeth (now Pfizer), is in Phase III trials. The drug is a dual kinase inhibitor, and unlike Gleevec, it inhibits the autophosphorylation of both Abl and Src kinases, resulting in inhibition of cell growth and cell death. Because of the dual mechanism of action, bosutinib, also known as SKI-606, may have activity in resistant CML disease, other myeloid malignancies, and solid tumors.

- Novartis is testing experimental cancer drug panobinostat in a number of Phase II and III trials for CML and other types of malignant disease. Panobinostat, also called LBH589, is a potent pan-DAC inhibitor, which has shown to induce cell death of tumor cell lines but not normal cells. According to Novartis, by interfering with the hallmarks of cancer, pan-DAC inhibitors have potential in many hematologic and solid malignancies.

Tags: cancer, clinical trials, leukemia, tyrosine kinase inhibitors