Combination Therapy May Reverse Venetoclax Resistance in Relapsed or Refractory AML

May 14, 2020 | Biotechnology

For your daily Biotechnology industry news, Lab.Equipment has curated this interesting article from GEN just for you:

After decades in which no novel therapeutic treatments were approved for acute myeloid leukemia (AML), the past few years have seen the approval of several groundbreaking therapies for the disease.1 One of the most rapidly adopted agents is venetoclax (ABT-199), which results in favorable response rates and improved overall survival when used in combination with hypomethylating agents or low-dose cytarabine. Venetoclax exerts its antitumor effects through inhibition of the antiapoptotic protein B-cell lymphoma-2 (Bcl-2), thereby restoring the cellular process of apoptosis.2,3

Unfortunately, as with all current therapies for AML, most patients treated with venetoclax will eventually relapse due to development of resistance mechanisms. For venetoclax, one resistance mechanism that may occur in tumor cells is the upregulation of other antiapoptotic pathway members such as myeloid cell leukemia-1 (Mcl-1) protein, thereby circumventing the inhibitory effect of venetoclax on Bcl-2.4–8 To overcome the development of resistance, rational combinations that target distinct antiapoptotic pathway members and can potentially lead to synergy have become an area of burgeoning translational research.

Combatting resistance to venetoclax

Hematological cancers are radiation sensitive. An example of this phenomenon is highly relevant to AML patients for whom venetoclax treatment has failed. Specifically, radiation-mediated DNA damage is known to result in a decrease in Mcl-1 protein levels.9,10 Delivery of therapeutic levels of total body irradiation via external beam, however, is difficult to implement in hematological malignancies such as AML without significant toxicity.

Alternatively, targeted delivery of radiation can be achieved by antibody radionuclide conjugates (ARCs), where an antibody is linked to a radioactive isotope such as iodine-131 (131I) or actinium-225... Read the complete article at the GEN Blog.

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