Developmental Pathways: A Key to Effective Treatments for Lymphoid Malignancies

The development of a complex organism like a human being requires highly choreographed activities that include growth and migration of cells as well as cell differentiation to perform essential functions and to communicate with each other. This requires the expression of specific proteins in space and time that allow for the different cell types, tissues and organs to develop properly. This is accomplished in part by having our DNA, which encodes all the proteins we make, turn specific genes on and off at the right time. A subset of our genes, known as developmental genes, mediate the conversion of cells to accomplish specific tasks.

The Bruton tyrosine kinase (BTK) gene encodes an enzyme of the same name that is essential for the development and normal function of B-cell lymphocytes, a type of blood cell that is part of our immune system through the production of antibodies and interactions with other immune activities, such as augmenting T-cell activity.

Developmental genes are being used as targets for malignancies that form in tissues whose development is guided by those genes. As you will read in this issue of CURE®, drugs that target the BTK enzyme have shown remarkable success in treating B-cell malignancies.

Since BTK is an enzyme known as a tyrosine kinase, it can be inhibited by kinase inhibitors. The first BTK inhibitor, Imbruvica (ibrutinib), was approved in 2014 for the difficult-to-treat mantle cell lymphoma and later for chronic lymphocytic leukemia (CLL), but not B- cell malignancies.

Imbruvica combined with Rituxan (rituximab), an anti-CD20 antibody that binds CD20 that is expressed on B cells, was then found to be better than stan- dard Rituxan plus chemotherapy, demonstrating that combination biologics could actually be quite effective.

Unfortunately, cancers tend to become resistant to kinase inhibitors because the part of the protein they bind to can be altered by tumor gene mutations. This has necessitated refinements in BTK inhibitors, with the next generation of these agents represented by Calquence (acalabrutinib) and Brukinsa (zanubru- tinib).

Not only are these drugs more effective at other B-cell malignancies like Waldenström macroglobulinemia, but they are also more selective for BTK as opposed to other kinases that govern many normal cellular processes, and therefore with fewer side effects, particularly on the heart.

The most recent approval for newer- generation BTK inhibitors is for Brukinsa to treat CLL, one of the most common lymphoid malignancies, and for small lymphocytic lymphoma. Two separate trials were the basis for these approvals on the basis primarily of MOR activity (tumor response and progression-free survival), including more aggressive cases with chromosome 17p abnormalities.

Personalized medicine means not only more powerful drugs for cancers, but also more precise mechanisms that target the specific consequence of mutations and other alterations that drive cancer cell growth, sparing normal cells. Our ability to design drugs rapidly and test them in the lab is accelerating, explaining the more rapid cadence of drug approvals. The BTK story is just one more, and we expect the list to keep growing.

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