Dr. Michael Caligiuri Explains Origins of Cancer at Annual Fireside Chat

Michael A Caligiuri Fireside Chat

Back when he was in medical school, Michael A. Caligiuri, MD, says there wasn’t much hope when a patient heard the words “you have cancer.”

“But today, everyone, especially everyone here, knows someone living successfully with cancer or cured of cancer,” said Dr. Caligiuri, at his Fireside Chat that is sponsored annually by JamesCare for Life. Dr. Caligiuri is the Director of The Ohio State University Comprehensive Cancer Center and CEO of the James Cancer Hospital and Solove Research Institute.

“There’s hope, so much hope now, but how did we change from the no hope of 35 or 40 years ago?” he asked the crowd of about 250 cancer survivors, caregivers and community members.

During his chat, Dr. Caligiuri took a step-by-step – and easy-to-understand – approach in explaining how cancer forms and grows in the body. Understanding this has led scientists at the OSUCCC – James and around the world to incredible breakthroughs in research and treatment that are prolonging and saving lives.

“Cancer is very simple in some ways, and very complex in others,” said Dr. Caligiuri, noting cancer is the body’s failure to regulate normal cell growth. “It’s a single cell that decided to not stop growing.”

For example, when a person gets a small cut, a signal is sent to all the cells in the area of the cut to start multiplying more rapidly to seal and repair the wound. “The oncogene signal goes from the surface of all these cells all the way to the nucleus and tells the cells to replicate themselves,” Dr. Caligiuri said.

When the cut is healed, another “set of receptors sends signals to the nucleus and says ‘stop, the factory is shut down,’” Dr. Caligiuri said, adding these are called tumor suppressor genes.

Cancer can occur when either “the lightbulb of one oncogene won’t shut off or one tumor suppressor gene won’t come on, because it’s blocked,” Dr. Caligiuri said.

It does get more complicated. It takes about 150 sequential signals, or what Dr. Caligiuri called “lightbulbs,” for the oncogene’s message to multiply to reach the nucleus of a cell, and then another 150 signals to shut down the “factory.” And, every time a cell divides, each and every one of the two billion chemicals contained in a cell (the DNA), must be replicated exactly.

This presents a lot of opportunities for mistakes, and for cancer to gain a toehold.

Take, for example, the simple process of a cell multiplying. It occurs millions of times every day in the body without a problem.

“The signal comes and the nucleus says, OK, all two billion base pairs, we have to duplicate ourselves,” Dr. Caligiuri said. He compared this to a word that’s two billion letters long, and if even one of the letters is wrong, “that’s a problem.”

However, every cell has a mismatch repair gene that Dr. Caligiuri compared to the spellcheck on a computer. The mismatch repair gene travels the length of each two billion-letter word, looking for and correcting any mistakes before the cell divides.

If a mismatch repair gene is broken, or is missing due to a genetic mutation, this could also lead to cancer.

“Could” is the key word because, even if the “light switch” (oncogene) is left on, the “brakes” (tumor suppressor genes) don’t work and the “spellchecker” (mismatch repair genes) misses a few letters, the body has another safety system in place: the immune system.

The immune system carefully surveys every new cell. “These T cells and killer cells have little molecules on their surface” that approach and “tickle” all these new cells, Dr. Caligiuri said. “And when they reach normal cells, these cells say ‘don’t kill me.’ These are called checkpoints.”

But cancer cells are clever. They can produce molecules on their surface that trick the T cells and killer cells into thinking they are normal cells. These are called checkpoint ticklers and they block the checkpoints on the T cells.

The good news is that all of the above has been discovered, is well understood and has led oncology researchers to develop scores of different ways to attack and destroy cancer cells. For example, checkpoint inhibitors are drugs that allow the immune system to recognize and attack cancer cells, and are key in the growing field of immunotherapy, which shows great promise.

“When I was in medical school, we had four or five (chemotherapy) drugs for everyone who had cancer, and it didn’t matter what type of cancer you had,” Dr. Caligiuri said.

This approach wasn’t very effective, as there is no routine cancer or “one-size-fits-all” cancer treatment. The discovery of the oncogene and tumor suppressor gene and their signaling processes has led to targeted therapeutics. Researchers have learned how to “turn this accelerator off and to replace this brake that is broken and get the cells to regulate themselves,” Dr. Caligiuri said, adding these signals in different oncogenes and mismatch repair genes vary in different patients.

One of the OSUCCC – James’ cancer research experts, David Carbone, MD, PhD, Director of The James Thoracic Oncology Center, was in the audience at the Fireside Chat.

Dr. Caligiuri told the audience Dr. Carbone was the first to discover one of the oncogenes responsible for lung cancer “and because of his discovery we’ve developed a targeted therapeutic … it’s created a whole revolution for targeted therapeutics for lung cancer.”

Genetic mutations can lead to someone missing a mismatched repair gene. An example of this is Lynch syndrome. About 5 percent of all colon cancer patients have Lynch syndrome. Men with it have a 90 percent chance of developing colon cancer and women have a 90 percent chance of developing colon cancer and a 60 percent chance of getting uterine cancer.

With funding from Pelotonia, the OSUCCC – James conducted a statewide survey of 3,000 colon cancer patients and their direct relatives who had yet to get cancer, screening them for Lynch syndrome. About 50 of these patients had Lynch syndrome and about 100 of their relatives had the genetic mutation.

The relatives will undergo early screenings that will detect pre-cancerous polyps before they become cancerous. It will save lives, and Dr. Caligiuri said the OSUCCC – James wants take the program national as part of the White House Cancer Moonshot initiative and save thousands more lives.

Next up in statewide initiatives, a Pelotonia-funded project at the OSUCCC – James will perform genetic screenings on tumor samples of all the lung cancer patients in Ohio. The goal is to find genetic mutations that can be treated with targeted therapeutics already developed and approved.

“It all comes back to research,” Dr. Caligiuri said, urging those in attendance to join Pelotonia as a rider, virtual rider, volunteer or donor. The annual bike ride has raised more than $130 million for research at the OSUCCC – James since it began in 2009.

“With your passion and commitment and courage, and that killer attitude, we’ll get this done and create a cancer-free world,” Dr. Caligiuri said.

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