Proteomics and the development of precision medicines against cancer (Part 3)

Cancer is a heterogenous mixture of diseases characterized by, among other things, the abnormal, uncontrolled growth of cells derived from otherwise healthy tissues (Hanahan 2022). Although cancer cells sometimes grow into balls of cells and stop there (so-called benign tumors), often they gain the ability to disperse throughout the body, seed the growth of other tumors, disrupt the function of a variety of organs, and ultimately kill patients. In this series of blog posts, we discuss how proteomics can drive the creation and use of “precision medicines” that target the processes enabling cancer growth and stop cancer in its tracks.

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The proteome and cancer treatment

When it comes to developing new cancer treatments, proteomics will accelerate research in a number of ways. These include:

• Prioritizing which mutant genes to target based on the abundance of the encoded proteins. Generally it is better to target proteins produced at a higher level in cancer cells as opposed to healthy cells. This can make drugs more selectively active on cancer cells and thereby decrease side effects and toxicity.

• Identifying potential targets downstream of a driver mutation. The protein encoded in a mutated gene may be difficult to target with a drug for a variety of reasons. By inserting this mutation into healthy cells and assessing how other protein levels change as a result, researchers can identify additional therapeutic targets. E.g. proteins whose production increases after the mutated gene is added to healthy cells and which have a known association with growth signaling might make good drug targets.

• Mining broad changes in post-translational modification and protein production. If proteins have different post-translational modifications in cancer cells or are produced at drastically different levels in cancer cells compared to healthy cells, they may be involved in the molecular mechanisms driving the cancer. Researchers can thus design drugs to alter these post-translational modifications or change the production of the aberrant proteins to determine if cancer cell growth is affected. If so, drugs targeting these modifications or proteins can be prioritized for testing in patients.

Once a therapeutic target has been established and validated through the clinical trial process, proteomics can continue to help doctors achieve more effective treatments. Proteomics can help doctors identify patients in which treatments are working well, in which cancer cells appear to be developing drug resistance, and in which treatments are failing.

To understand how this is useful, it’s informative to look at one of the most effective precision medicines developed to date, the anti-cancer drug, Imatinib (Hochhaus 2017). This drug was developed to treat a cancer of the immune system called “Chronic Myeloid Leukemia” or CML. As discussed in the first post in this series, CML manifests when a translocation between 2 chromosomes creates a fusion of the genes bcr and abl. The BCR-ABL fusion protein encoded in this gene continuously signals for cells to grow and drives cancer progression.

Upon discovering the causal role of BCR-ABL in CML, researchers set out to develop drugs that could inhibit its activity. They searched through a library of chemicals to find compounds that did just that and, after finding a promising hit, optimized this compound to be more easily delivered to the body and to act more selectively on BCR-ABL and not other, similar proteins. Imatinib was the result and, although it takes months for its effects to be achieved, many patients respond incredibly well to this precisely targeted drug (Sacha 2014, Hochhaus et al 2017).

Unfortunately, Imatinib does not work in all patients. Some of them have cancer cells that produce “efflux pump” proteins which pump the drug out before it can have beneficial impacts (Illmer et al 2004). Others have additional mutations in the bcr-abl fusion gene that prevent imatinib from interacting with the fusion protein productively, and still others have mutations that increase production of the  BCR-ABL protein (Hochhaus et al 2002, Osman and Deininger 2021).

Researchers have created Imatinib successors that retain their activity in the face of many of these resistance mechanisms. However, many years of additional research were required to elucidate the mechanisms of resistance and optimize these newer drugs. Even so, some of these newer compounds have stronger side-effects than Imatinib and may be risky for some subgroups of CML patients to take (Osman and Deininger 2021). In addition, Imatinib and its successors are only effective during the early, less aggressive stages of CML. If patients advance beyond this stage, drug resistance is common and further progression is often BCR-ABL independent because the cancer cells acquire additional driver mutations. Finally, even when successfully treated, most patients must keep taking Imatinib or one of its successors for life to avoid relapse. This can be very expensive and efforts are ongoing to determine what distinguishes patients who don’t relapse from those who do.

Given the above issues, even in the face of tremendous success, proteomics can accelerate and enhance the development of precision medicines like Imatinib in a number of ways. These include: