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CDK Inhibitors: Why Women - and Men - Should Know About This ‘New Era’ Of Cancer Treatment

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From wearing pink to correctly identifying the ribbon, breast cancer has an ingrained cultural presence. Both the color pink and the cancer ribbon are also reminders of just how common the disease is: breast cancer remains the second most common cancer for women in the United States (second only to skin cancer) and the second leading cause of cancer death for women in the United States (second only to lung cancer).

Despite this global acknowledgement of the presence of breast cancer, an understanding of the treatment options for breast cancer - or any other cancer - doesn’t always follow. PBS NewsHour found that those who have actually been diagnosed with cancer have often been confused by medical terms, unable to comprehend the severity of their case, or too overwhelmed to talk through different treatment options.

As a result, another way to support cancer patients – beyond wearing pink or a breast cancer ribbon – is to increase overall health literacy, such as learning about different types of cancer treatment options. And one option in particular might be ushering in a “new era” of treatment: cyclin-dependent kinase (CDK) inhibitors.

Treatments Today:

Cyclin-dependent kinases (CDKs) regulate a healthy cell cycle; the activation of these enzymes helps the cell divide. If a cell becomes cancerous, though, the work of CDKs can cause the proliferation of the cancer, allowing cancerous cells to continue to divide, multiply, and spread throughout the body.

CDK inhibitors are a type of cancer treatment - a drug such as the ones given during chemotherapy - to block this activity, inhibit this cell division, and slow the growth and spread of cancer cells. Since 2015, the Food and Drug Administration has approved three types of CDK inhibitors (abemaciclib, palbociclib and ribociclib) for CDK 4 and 6: two enzymes that represent the “driving force” of cancerous tumor formation in several different cancer types. These drugs are currently used to treat only one specific type of cancer: hormone receptor positive (HR+) ERBB2 negative (ERBB2-, formerly known as HER2-) metastatic breast cancer, which is the most common subtype of breast cancer for women.

Despite these CDK inhibitors’ relatively limited use, one article notes that their development is “arguably one of the most clinically important discoveries” for patients with HR+ ERBB2- breast cancer patients. Treating them with a combination of hormone therapy and a CDK 4/6 inhibitor can give them more time (roughly 12 months) before the cancer spreads and higher survival rates overall than those treated with hormone therapy only.

Encountering resistance:

CDK inhibitors do face a potential obstacle, though: the cell’s ability to build resistance to the inhibitors.

Cancer cells that aren’t killed off by the prior lines of treatment can develop resistance to those very same treatments, limiting their effectiveness in the future. This resistance is not unique to CDKs and CDK inhibitors: for example, a new flu shot is available every year because the flu virus may have developed immunity to prior year’s shot, mitigating its usefulness.

For context, the World Health Organization estimates that 290,000 to 650,000 people die of flu-related causes every year worldwide. For cancer, that number is around 10 million - and, as a 2019 article in Nature summarized, “Drug resistance continues to be the principal limiting factor to achieving cures in patients with cancer.” For CDKs specifically, if CDK4 is inhibited - such as through a cancer treatment - CDK2 will take over its role and propagate the cancerous cells. Those cells not only will continue to grow but also will be resistant to prior CDK inhibitor treatments.

One hypothetical way to mitigate the effect of CDK2 is to target it individually: with a CDK inhibitor that is unique to it. The reality is that CDK2 has a receptor “pocket” identical to that of CDK1, which is an essential protein. A drug that accidentally fills CDK1’s pocket instead of CDK2’s can prevent intestinal cell replication and lead to gastrointestinal (GI) issues. It could also prevent replication of blood cells and decrease the body’s ability to fight disease. Because of this risk, there have been only limited (and unsuccessful) attempts to target CDK2 specifically – and even those few tests have resulted in millions of dollars of losses due to the expenses of conducting an oncology clinical trial, even in its first (earliest and cheapest) phase.

“Better Days and More Days”

Another solution is to target CDK2 not on its own but with CDK4 to prevent the former from taking the latter’s role in cancer cell proliferation,

One company taking this approach is Concarlo Therapeutics, which is developing a novel type of CDK inhibitor based on the p27 protein, which helps regulate CDKs 2, 4, and 6. Dr. Stacy Blain, Concarlo Therapeutics co-founder and chief scientific officer, was one of the first people to work on researching the p27 protein and is now one of the world experts on it. She compares p27 to a door; when it swings open, the CDKs are activated and allow cells, including cancerous cells, to divide and multiply. When p27 swings shut, the CDKs are inhibited, helping to minimize the spread of cells. A healthy body performs this regulation naturally.

Concarlo Therapeutics aims to develop a cancer treatment that builds on the natural and healthy functioning of p27: using it to inhibit both CDK2 and 4 and to slow the spread of cancer, starting with breast cancer and potentially building towards endometrial, ovarian, pancreatic, and non-small-cell lung cancers as well. The company’s peptide product is sealed inside a lipid suitcase that protects the peptide from degradation as it travels to the tumor site. Because p27 naturally inhibits CDK4 and CDK2 more than CDK1 or any other essential protein, an approach utilizing this protein is more specific and less toxic than other CDK 2-focused drugs.

As Dr. Blain notes, the ultimate goal for cancer treatments, including Concarlo’s, is to create “drugs that give better days and more days”. In other words, drugs with less associated toxicity than previous – or current - options can give patients more and higher quality time than they might have had otherwise. For patients with endometrial and ovarian cancer specifically, this additional time has another benefit: the ability to make informed decision – rather than a rushed, spur-of-the-moment one – about a treatment option that may affect their reproductive capabilities and subsequent mental health.

Increasing Health Literacy:

In 2013, one published study was titled, “Breast Cancer Treatment Decision-Making: Are We Asking Too Much of Patients”? It found that “health literacy” problems - an individual’s ability to find, understand, and use information to guide their healthcare decisions and to adhere to their treatments - were most common among cancer patients who felt like they had too much or too little responsibility for their treatment decision-making.

10 years later, as cancer cases and costs continue to rise, innovative companies like Concarlo Therapeutics and others are helping to increase potential treatment options and positive outcomes for patients. The next step, however, is for individuals to understand these potential options and outcomes themselves: be they scientists who work for the National Institutes of Health (NIH) to push for and capitalize on funding for cutting-edge biomedical research or simply individuals who might encounter cancer in some form themselves. After all, 40% of United States adults will be diagnosed with cancer at some point in their lives. Knowing the pros, the cons, and the science behind treatments, like CDK inhibitors, can help these individuals improve their health and health literacy, overcome any confusion or incomprehension they may face otherwise, and make informed healthcare decisions in the future - just as easily as they might wear pink or identify the breast cancer awareness ribbon today.

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