Metastatic breast cancer, CDK inhibitor research continues
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In recent years the prospects of those who have a metastatic breast cancer have changed profoundly. The credit goes mainly to a class of drugs that interfere with a family of proteins vital to early cell development, the cyclin-dependent kinases (CDKs). By targeting this target, CDK inhibitors prevent the division and multiplication of cancer cells. The first generation of these drugs – ribociclib, palbociclib, abemaciclib – target two proteins: CDK4 and CDK6.
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The results of the studies that led to the registration of these drugs and also those collected in clinical practice – the so-called real life – show that the addition of these molecules to hormone therapy produces a significant lengthening of the time that patients spend without the disease progress.
Over the years, studies have also been conducted to verify whether anticipating treatment with these molecules could represent an advantageous strategy. And also in this case the response was positive: taking CDK4/6 inhibitors immediately after surgery decreases the risk of the disease progressing. A protection that also translates into a lower mortality of the patients who receive them.
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So all right? Not exactly. Most patients do not respond to these drugs and, even when they do work, side effects and the development of resistance limit their effectiveness. That’s why scientists are looking for new, more effective and less toxic CDK inhibitors. The latest innovations in this field were recently presented during the American Society of Clinical Oncology (ASCO) congress, the main scientific event for oncologists from all over the world.
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The new generation
One of the studies presented in Chicago concerned a new molecule, PF-0722006, capable of selectively targeting CDK4 and not CDK6, and thus being less toxic. To present the data was Timothy Yapassociate professor of Investigational Cancer Therapeutics at MD Anderson, the research center where another CDK4/6 inhibitor is being studied, ribocicliband where the team led by Gabriel Hortobagyi made the history of breast cancer therapies.
“The next generation of CDK inhibitors are more selective and potent and only block CDK-4. By removing the inhibition of CDK6 we see less toxicity and we are able to increase the dosage as well, thus achieving greater efficacy,” he explained.
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The researchers reported that they observed fewer cases of neutropenia, the lowering of the levels of circulating neutrophils which leads to an increased risk of contracting infections. As a result, they could administer more drug than the tolerated CDK4/6 dose.
“The results from preclinical models tell us that PF-0722006 suppresses tumor growth in models that are resistant to the action of the combination of first-generation CDK4/6 inhibitors with endocrine therapy,” Yap said.
Change targets
Preliminary results, but nonetheless encouraging, which indicate the possibility of overcoming resistance and being effective even in patients who have already received CDK4/6 inhibitors until they no longer obtain benefit. But in addition to better targeting CDK4, research is focusing on a new target, CDK2. Also in Chicago, Yap presented the first results of the experimentation of another molecule, PF-07104091, a new and powerful selective inhibitor of this protein never targeted until now.
There are also many data indicating that some tumors express high levels of some biomarkers, for example CDK2 but also cyclin E. The two molecules interact by binding during the early stages of the cell cycle and the excessive production of cyclin E appears to be the main driver of degeneration leading to cancer.
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Hitting the mark
The new data on CDK2 is encouraging because not much has been achieved so far. The pocket where the drug that destroys CDK2 attaches is very similar to that of another protein of the family, CDK1, which however is also essential for the life of healthy cells and therefore cannot be inhibited. Therefore, a drug that misses the target would cause many side effects, especially at the gastrointestinal and immune level. A risk that appears to be lower if CDK2 and 4 are combined. In short, the road to research is still long, but the premises are there for being able to improve a family of molecules that has already given new hope.
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