Understanding ROR1

ROR1, an oncogene recently discovered on chronic lymphocytic leukemia (CLL) B cells, is being studied by researchers as a potential target for CLL treatment. Dr. Brian Koffman met with Dr. Thomas Kipps, who is researching ROR1, at the 2014 American Society of Clinical Oncology (ASCO) meeting to discuss this oncogene and its potential use in treating CLL.

Click HERE: https://www.youtube.com/watch?v=Zji6Fux_WGo

Thanks to Patient Power!fig1

 

Removing the Block and ABT199

 

By Michael Choi, M.D. 

Chronic Lymphocytic Leukemia (CLL) has been described as a relentless accumulation of leukemic cells due to an imbalance of excessive cell proliferation and defective cell death. In other words, CLL cells have both “pro-survival” and “anti-death” mechanisms. In a previous article, we described the pathways on the pro-survival side, such as the B-cell receptor associated tyrosine kinases, and clinical trials of agents that block those pathways. In this article, we will focus on the opposite side of the equation: the mechanism by which CLL cells escape cell death, and how new therapies can overcome it.

Cell death is normally tightly regulated by proteins in the B-cell lymphoma/ leukemia 2 (BCL-2) family. BCL-2 sequesters and disables the proteins BAX and BAK, which when left free of BCL-2, signal a cell to die. When normal cells or their DNA are damaged, BCL-2 is bound and occupied by other signals, thus freeing BAX and BAK to trigger cell death. CLL cells (and other cancerous cells) have extremely high levels of BCL-2, to the point that its grasp on BAX and BAK cannot be overcome.

In recent years, therapies that inhibit BCL-2 have been designed and largely pioneered by our group and collaborators in the CLL Research Consortium. The pharmaceutical company Abbott has developed and refined drugs that inhibit BCL-2, including ABT-737, ABT-263, and ABT-199. In a phase 1 study treating patients with relapsed CLL, ABT-263 was strikingly effective: 90% of patients experienced a significant decrease in lymphocyte counts and the median progression-free interval was over 2 years. (Roberts, Seymour, Brown, Wierda, Kipps, et al. JCO, 2011)

Although very well tolerated overall, the most common adverse effect of ABT- 263 was a decrease in platelet counts due to the inhibition of one particular BCL-2 family member that is important for platelet function. Due to this, ABT-199 was developed to avoid this effect on platelets. Trials of this oral drug are ongoing, both alone and combined with other agents. Although these are early phase studies (phase 1 and 2), our years of experience with Abbott compounds and the clinical proof that blocking BCL-2 is an effective treatment make us confident that these new agents will represent a significant step towards our goal of curing this disease.