New Hope for Hard-to-Treat Breast Cancers

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THE NOBEL PRIZE in Physiology or Medicine—rarely interesting or comprehensible to most lay people—has been a hot topic around town this year, spilling into Starbucks wait lines and the early minutes of yoga class where talking is generally discouraged.

Although the prize goes to basic research and is often presented years after the first publication of results—so not breaking news—work by the 2019 winners offers new hope for the treatment of the most aggressive breast cancers.

In addition, the focus of this year’s research—decreased oxygen levels in cancer cells—may also lead to improved treatments for cervical cancer and other tumors induced by human papillomaviruses (HPV), blamed for 5% of all cancers worldwide, including those of the head, neck and reproductive tract.

Low oxygen levels transform some cancer cells so that they behave much like embryonic stem cells—immature cells known for their ability to multiply indefinitely and give rise to “progenitor cells,” which mature and populate the body’s tissues during embryonic development.

“Oxygen-poor environments like those often found in advanced human breast cancers serve as nurseries for the birth of cancer stem cells,” according to Johns Hopkins geneticist and Nobel Prize winner Gregg Semenza.

Contrary to the earlier view that cancer cells located deep in tumors and deprived of oxygen were dying, they turned out to be merely dormant, sleeper cells that in hypoxic conditions were in the process of acquiring new powers as stem cells.

The same low oxygen levels allow these cancer cells to evade treatment. Based on other research, Arizona pharmacology researchers noted that “tumor hypoxia is a prevalent and major obstacle to effective cancer treatment with radiotherapy, chemotherapy and immunotherapy.”

Once newly empowered, cancer stem cells travel to distant regions of the body where they create dangerous metastases. Investigations into what the cancer cells are searching for as they spread into surrounding tissues and then into blood cells spurred Semenza and colleagues to consider oxygen—and in turn to identify those cancer cells capable of thriving in low oxygen conditions as stem cells that can help tumors spread.

“The search has been intense to find these cells’ Achilles heel…so they would no longer have the power to keep repopulating tumors,” Semenza told Johns Hopkins News.

That Achilles heel may be the molecular on-off switch discovered by the prize winners, which controls the cancer cells’ response to low oxygen levels. Interfering with the genes involved in that switch could reduce the number of dangerous cancer stem cells that migrate and cause metastases.

At least two drugs now in clinical trials focus on reversing tumor hypoxia, one of which improves the permeability of oxygen into the tumor tissue.

Drugs currently on the market based on a similar understanding of oxygen-sensing pathways work to increase both red blood cell production in cases of anemia, and oxygen levels for patients with lung and heart disease.

In 2018, the Nobel Prize in Physiology or Medicine also went to cancer treatment researchers, and a documentary portraying the life and work of one—“Jim Allison: Breakthrough”—is currently playing in D.C. theaters.

Research by Allison, professor of immunology at the MD Anderson Cancer Center, and colleagues led to the first checkpoint inhibitor drug, a “breakthrough” in the treatment of advanced melanoma, which helped spawn recent advances in immunotherapy—that requires overriding inhibitor molecules on cancer cells to allow a patient’s own immune system to attack them.

Precision medicine, seen as the future of cancer treatment, will likely depend on assessments of multiple biomarkers, with an important one being the location of hypoxic microregions throughout tumors.

—Mary Carpenter

Every Tuesday, well-being editor Mary Carpenter reports on health news you can use.