Patients with a type of liver cancer known as hepatocellular carcinoma (HCC) face a stressful time after their tumor is removed. In about half of these people, the cancer returns within 2 years after surgery or heat treatment. Researchers have not identified treatments that prevent relapse.

That’s thanks to a class of drugs that were once seen as a failed revolution in cancer treatment. Angiogenesis inhibitors, which attack tumors by cutting off their blood supply, did not fare as well as expected when they arrived in clinical trials 2 decades ago. But now they’re getting an even more exciting story from a new class of drugs: checkpoint inhibitors, which unleash the immune system’s T cells to attack tumors. At last month’s American Association for Cancer Research (AACR) meeting, researchers discussed the combination of angiogenesis inhibition and checkpoint inhibition in HCC. They provided evidence of delayed recurrence in existing patients, a first for this type of cancer.

If the two parties receive approval from the US Food and Drug Administration (FDA), it will be the eighth drug combination OK’d in the last 4 years. More than 200 clinical trials are testing this approach in various types of cancer. Evidence suggests that angiogenesis inhibitors help cancer-fighting T cells enter tumors. “There’s a clear rationale for putting these two types of drugs together,” says Robert Kerbel, an oncologist at the University of Toronto.

This resurgence for angiogenesis inhibitors comes after stellar research expectations for the drugs faded in the late 1990s. Their origins were plausible. Tumors, starved of oxygen and nutrients, need to stimulate new blood vessels to sprout and grow; By preventing the formation of these vessels, angiogenesis inhibitors must starve tumors and inhibit their growth. But the drugs failed for a variety of reasons. These include the use of other methods to treat tumors or obtain blood. “It was an omnipotent disaster,” said Francesco Pezzella, a tumor researcher at the University of Oxford, whose team discovered that tumors can be ordered instead of producing new vessels.

Still, angiogenesis inhibitors have achieved some success. The monoclonal antibody bevacizumab received regulatory approval in 2004 for patients with advanced colon cancer, and more than a dozen other angiogenesis inhibitors have joined the antitumor arsenal. But by themselves, angiogenesis inhibitors only add a few months to patients’ lives. “They’re great at controlling disease, but they’re not cures by themselves,” says medical oncologist Brian Riney of Vanderbilt University Medical Center.

Scientists have always combined approved cancer drugs to test whether they work best in concert, but a breakthrough 25 years ago explains why the checkpoint inhibitor-angiogenesis inhibitor partnership is so effective. The blood vessels in the tumor are messy—irritating, twisting, and leaking. In the year In the late 1990s, Rakesh Jain, a tumor biologist at Harvard Medical School (HMS), noticed that angiogenesis inhibitors had a surprising effect on tumors. The drugs “normalized” the vessels, causing them to become narrower, straighter and have a smaller hole. “All I saw were veins. [inside tumors] In the year said Jain, who published his “vascular normalization” hypothesis in 2001. Although initially controversial, the explanation is now widely accepted, says Oxford cancer biologist Annette Magnuson.

Abnormal blood vessels leave the inside of a tumor with low oxygen levels, preventing any T cells from attacking the tumor. Those disabled are checkpoint inhibitors, which work by preventing cancer cells from overwriting the suppressors on T cells. By restoring normal blood flow to the tumor, angiogenesis inhibitors reverse immunosuppressive factors, allowing tumor-targeting T cells to inject. Gene normalization of tumor vessels can provide another benefit – strengthening metastasis, the spread of tumor cells to other parts of the body. An oxygen-starved tumor is “like a wounded tiger,” he says. In that case, it is more dangerous, because it is prone to release cells that can be transferred to another place and form new tumors.

To date, dozens of clinical trials have evaluated checkpoint inhibitor-angiogenesis inhibitor combos. Some have proven to be toxic, and others have failed. However, the studies have led the FDA to approve new treatments for liver, kidney, lung and endometrial cancers. The medicinal compounds are not curative, but they prevent tumor growth. And some extend patients’ lives by several months with angiogenesis inhibitors alone.

Other trials have also shown promising results, including HCC, which liver surgeon Pierce Chow of Duke NS Medical School in Singapore presented at the AACR meeting. In a phase 3 trial, the combination of bevacizumab and the checkpoint inhibitor atezolizumab reduced the chance of tumor recurrence after surgery or heat therapy by 28 percent in patients whose disease was diagnosed early. The researchers are still following the patients to see if these benefits persist and if the combination increases survival.

Scientists aren’t just mixing and matching existing options. At least one startup, DynamiCure, is seeking to develop new angiogenesis-blocking drugs that are safer and can be combined with checkpoint inhibitors. The company has begun a clinical trial of an antibody that stimulates vessel normalization. “When new companies are founded, the field is not dead, it’s blooming.

Still, the strategy of combining the two types of medicine faces many challenges. For one thing, most angiogenesis inhibitors directly or indirectly stymie vascular endothelial growth factor (VEGF), which promotes blood vessel growth. However, normal tissues need VEGF, and the drugs can cause side effects such as bleeding, high blood pressure, and high blood pressure.

In addition to side effects, researchers need better ways to determine whether tumors are responding to drug duos, says Magnuson. “The challenge of using this [strategy] How to cost-effectively and time-efficiently monitor arterial normality in humans.

H.M.S. “We’re making the same mistakes we made the first time,” he said, along with anticonvulsants.

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