Dr. Charis Teh and colleagues presented this research at the American Society for Hematology annual meeting, which was held in December 2021 (ASH 2021).
Background:
Venetoclax is a highly effective treatment for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) that works by inhibiting the BCL2 protein. BCL2 is a protein that helps control whether a cell lives or dies by blocking a type of cell death called apoptosis. In CLL / SLL, BCL2 is made in larger amounts, keeping cancer cells from dying. BCL2 inhibitors, such as venetoclax, bind to the BCL2 protein and block its action leading to cell death.
However, despite continuous treatment, the disease will continue to progress in some patients. This is likely because cancer cells can mutate and develop drug resistance. See our previous interviews with Dr. Adrian Wiestner and Dr. Constantine Tam for more information on the concept of clonal evolution. In this study, researchers sought to understand what changes are happening in patients starting venetoclax therapy at the cellular level.
Takeaways:
- Researchers collected blood samples from patients with relapsed/refractory CLL before treatment and during venetoclax dose escalation.
- The blood samples were analyzed using mass cytometry, which is similar to flow cytometry except that it uses heavy metal ion tags instead of light-sensitive dyes.
- Researchers measured changes in 43 regulators of immune cells, cell death, proliferation, cell signaling, and cancer-related pathways at the single-cell resolution.
- After six weeks of treatment with venetoclax, the CLL burden in the peripheral blood decreased dramatically.
- The remaining CLL cells had increased protein expression of BCL2, and this effect was dose-dependent, meaning that as the dose of venetoclax increased, the amount of BCL2 expressed by the CLL cells also increased.
- The remaining CLL cells also had increased expression of the chemokine receptor CXCR4.
- CXCR4 is typically involved in signaling pathways that control cell migration and cell proliferation. Overexpression of CXCR4 in cancer contributes to tumor growth, invasion, angiogenesis, metastasis, relapse, and therapeutic resistance.
- There were proportional increases in healthy T cells as the CLL burden was reduced with venetoclax treatment.
Conclusions:
Targeted therapies are highly specific so that they only kill certain cells, but this also means that if there is a cancer cell with a resistance mutation, it can evade treatment and multiply. As we see in this study, venetoclax kills most CLL cells, but some survive, and these cells increase the expression of proteins that help them survive. Furthermore, striking changes in the wiring of survival pathways in CLL cells occurred shortly after venetoclax treatment, suggesting that therapies targeting other survival pathways should be considered shortly after dose-escalation.
Here is the link to the ASH 2021 abstract for more details.
Take care of yourself first.
Ann Liu, PhD
