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How Targeted Cancer Drugs Disrupt the Cell Cycle

“If you’re an adult with newly diagnosed non-small cell lung cancer that’s spread and tests positive for PDL1 without an abnormal EGFR your first option could be …” announces a TV ad for a pair of targeted cancer drugs, flying by so fast that I doubt many patients can grasp anything.

According to the FDA, the wording of the ads comes from a ”research team of social psychologists.” Science journalists might better communicate drug mechanisms to consumers.

Another way to fathom the info in cancer drug ads is to go back to high school biology and consider the cell cycle – the molecular choreography that tells a cell whether, when, and how often to divide. The cycle has offshoots, called checkpoints, which enable a cell to die by apoptosis (aka programmed cell death) or pause for a time-out. Many targeted cancer drugs interrogate cell cycle enzymes and proteins that oversee checkpoints, stopping runaway cell division.

Remembering IPMAT

Older cancer drugs – adriamycin, cyclohexamide, cisplatin, methotrexate, and a host of others – obliterate any rapidly-dividing cells. In contrast, targeted drugs interrogate specific molecules that cause or drive a cancer by recognizing molecules that are more abundant on, or more active in, or function differently in, cancer cells, properties that arise from mutation. In most cancers, mutations in oncogenes or tumor suppressor genes are only in the affected cells. Inherited cancers, in which one mutation is present from fertilization, are rare. (I explain this classic 2-hit hypothesis in my post about my breast cancer, here.)

An actively dividing cell doubles and reapportions its chromosomes into two daughter cells from the original one – this is mitosis. The rest of the cell cycle is interphase. Remember memorizing the stages for exams? Interphase, prophase, metaphase, anaphase, telophase, and interphase again, IPMAT. But for those who don’t pursue careers in biology or health care, the memory of “IPMAT” vanishes when the exam is over. And it’s an artificial construct to capture a continuous process.

My daughter Heather was fortunate to encounter IPMAT as a preschooler, when she sat behind the podium as I lectured several hundred undergrads at SUNY Albany many years ago.

Flash forward to seventh grade. The biology teacher is introducing cell division. And Heather begins to mutter a mantra: interphase, prophase, metaphase, anaphase, telophase, and interphase again.

“Heather, how do you know that?”

“Doesn’t everyone?”
she answered. It must have been challenging being my kid.

I recalled Heather’s early mastery of mitosis last week when the news reported promising clinical trial results for a cancer drug for brain tumors that targets a protein, called survivin, that controls the cell cycle. Older targeted cancer drugs harness kinases, which are enzymes that signal mitosis through undulating interactions with yet another protein, a cyclin. The new mantra is survivin, kinase, cyclin.

A Primer on the Cell Cycle

I’ve described the cell cycle in 38 textbook editions. Here’s a synopsis.

Exquisite control of the cell cycle maintains body form, keeping organs from shrinking or overgrowing. The cell division rate varies in different tissues and at different times. A cell lining the small intestine’s inner wall divides frequently, throughout life; a neuron never divides. A cell in the deepest skin layer may continue mitosis for awhile even after death.

Frequent mitosis drives the rapid growth of the embryo and fetus. Mitotic rate slows in older people, which may explain why cancer incidence drops for people in their 80s and older.

Control of mitosis is vital. Quadrillions of divisions occur over a lifetime, and not randomly. When and where a somatic cell divides is crucial to health. Too little mitosis, and an injury goes unrepaired; too much, and a tumor grows.

Groups of interacting proteins form the checkpoints, ensuring that chromosomes are correctly doubled and apportioned into two cells. A “DNA damage checkpoint” rests the cell cycle while special proteins repair damaged DNA. An “apoptosis checkpoint” turns on as mitosis begins. This is when survivins override signals telling the cell to die, propelling mitosis while blocking apoptosis. Survivin is part of the complex of proteins that attaches chromosomes to the spindle structure that parts them, stretching the cell into a dumbbell shape that then pinches off the two daughter cells from the original one.

While the events of cycling unfold, cells adhere to a built-in clock, their chromosome tips – telomeres – whittling down some 40 to 60 times. A connective tissue cell from a fetus will divide about 50 more times. A similar cell from an adult divides only 14 to 29 more times.

Throughout the cell cycle, cyclin and kinase proteins pair and part in ways that activate the genes whose products carry out mitosis. Cyclin levels fluctuate regularly throughout the cell cycle, while kinase levels stay the same. A certain number of cyclin-kinase pairs turns on the genes that trigger mitosis. Then, as mitosis begins, enzymes degrade the cyclins. The cycle starts again as cyclin begins to build up during the next interphase. Several cancer drugs target cyclin-kinase pairs.

A New Targeted Cancer Drug, Vorasidenib

A report of encouraging clinical trial results to treat a type of glioma, a slow-growing brain tumor, in the June 4 New England Journal of Medicine prompted this blog post. The candidate drug, vorasidenib, is a small molecule that inhibits survivin. It is intended for cancer cells that have mutations in genes IDH1 or IDH2, which encode enzymes that act in the Krebs cycle, a cellular energetics pathway (something memorized for biology exams too). Mutation blocks cells from maturing, trapping them in a state of more frequent division.

Cancer cells make too much survivin, with levels increasing as the disease spreads and becomes more aggressive. It’s long been recognized as a drug target.

Survivin inhibits apoptosis and promotes mitosis, so in excess a tumor forms. The earliest mention of survivin I could find was in a journal written in Polish with no abstract. Here’s an article from 2002.

The researchers tested the survivin blocker vorasidenib in 331 people. It delayed disease progression and more than doubled survival time, adding 17 months.

An Early Targeted Cancer Drug: Gleevec

The report on the new brain tumor drug reminded me of the astonishing success of one of the first drugs to intervene in the cell cycle, Gleevec (imatinib). It blocks the action of a tyrosine kinase, which transfers high-energy phosphate groups to specific molecules, sending a message to divide. Gleevec was developed to treat chronic myelogenous leukemia (CML). It is a cyclin-dependent kinase.

Gleevec came from a massive effort throughout the 1980s to screen more than 400 small molecules for one that would block the activity of the errant tyrosine kinase, without derailing other important enzymes. The compound that would become Gleevec, the first tyrosine kinase inhibitor, was discovered in 1992. The drug nestles into the pocket on the tyrosine kinase that must bind ATP (which provides energy) to stimulate cell division. With ATP binding blocked, cancer cells do not receive the message to divide, and they stop.

After passing safety tests, Gleevec worked so well that it set a new record for drug approval—10 weeks, on May 10, 2001.

I had the privilege to meet one of the first people to receive Gleevec, which I wrote about for Bioethics Today in 2006.

I visited Erin Zammett Ruddy at the headquarters of Glamour magazine in Manhattan, where she was an editor. She’d agreed to share her story for my human genetics textbook – not only was her recovery from a disease she hadn’t even known she had spectacular, but the background behind the story of Gleevec recounts a classic tale in the field, which I’ll get to soon.

When Erin was 23, a routine physical exam – she hadn’t gone for awhile because she was so healthy and athletic – revealed CML. Blood cancer. She chronicled her journey in Glamour and in My So-Called Normal Life, a book published in 2005.

When she was diagnosed, Erin looked the picture of health, a tall, striking natural redhead. She sent me a photo of her grimacing while having a bone marrow aspiration for my textbook back in 2006.

Thanks to Gleevec, Erin never went bald, never bruised, never felt too tired to work, and had children. The chromosomal glitch in her cancer cells that had juxtaposed two genes in a way that caused and drove the cancer vanished. Erin became a spokesperson for the Leukemia and Lymphoma Society. Gleevec has since been approved for several other cancers – it saved the life of one of my friends – as well as similar drugs that work if resistance to Gleevec develops.

Although Gleevec was approved in 2001, its development began on August 13, 1958, when two men entered hospitals in Philadelphia, complaining of weeks of fatigue. Like Erin, they had CML. Blood samples wound up in the lab of Peter Nowell, a young assistant professor at the University of Pennsylvania. He and his graduate student, David Hungerford, found in those aberrant white blood cells a clue: a small, unusual chromosome, eventually dubbed the Philadelphia chromosome, behind CML. The breakpoints of the unusual chromosome revealed what would become the molecular target of Gleevec. Nowell tells the Philadelphia chromosome story. It is a classic in medical science.

The stories behind the development of Gleevec and the new drug for brain tumors illustrate vividly the value of basic research.

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