Two promising new cancer treatments

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This experimental drug could change the field of cancer research

A tiny group of people with rectal cancer just experienced something of a scientific miracle: their cancer simply vanished after an experimental treatment.

In a very small trial done by doctors at New York's Memorial Sloan Kettering Cancer Center, patients took a drug called dostarlimab for six months. The trial resulted in every single one of their tumors disappearing. The trial group included just 18 people, and there's still more to be learned about how the treatment worked. But some scientists say these kinds of results have never been seen in the history of cancer research.

Dr. Hanna Sanoff of the University of North Carolina's Lineberger Comprehensive Cancer Center joined NPR's All Things Considered to outline how this drug works and what it could mean for the future of cancer research. Although she was not involved with the study, Dr. Sanoff has written about the results.

This interview has been lightly edited

On her first reaction to the results:
I mean, I am incredibly optimistic. Like you said in the introduction, we have never seen anything work in 100 percent of people in cancer medicine.

On how the drug works to treat cancer:
This drug is one of a class of drugs called immune checkpoint inhibitors. These are immunotherapy medicines that work not by directly attacking the cancer itself, but actually getting a person's immune system to essentially do the work. These are drugs that have been around in melanoma and other cancers for quite a while, but really have not been part of the routine care of colorectal cancers until fairly recently.

On the kinds of side effects patients experienced:
Very, very few in this study - in fact, surprisingly few. Most people had no severe adverse effects at all.

On how this study could be seen as 'practice-changing':
Our hope would be that for this subgroup of people - which is only about five percent to 10 percent of people who have rectal cancer - if they can go on and just get six months of immunotherapy and not have any of the rest of this - I don't even know the word to use. Paradigm shift is often used, but this really absolutely is paradigm-shifting.

On why the idea of being able to skip surgery for cancer treatment is so revolutionary:
In rectal cancer, this is part of the conversation we have with someone when they're diagnosed. We are very hopeful for being able to cure you, but unfortunately, we know our treatments are going to leave you with consequences that may, in fact, be life-changing. I have had patients who, after their rectal cancer, have barely left the house for years - and in a couple of cases, even decades - because of the consequences of incontinence and the shame that's associated with this.

On next steps for the drug:
What I'd really like us to do is get a bigger trial where this drug is used in a much more diverse setting to understand what the real, true response rate is going to be. It's not going to end up being 100 percent. I hope I bite my tongue on that in the future, but I can't imagine it will be 100 percent. And so when we see what the true response rate is, that's when I think we can really do this all the time.

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A new molecule kills hard-to-treat cancers in tissue samples and mice, study shows.

A new lab-designed molecule that exploits a weakness in cells can kill a wide range of cancers that are difficult to treat, according to a new U.S. study conducted on human cancer tissue and in human cancers grown in mice.

The study, published on June 2 in the peer-reviewed journal Nature Cancer, found that the compound, ERX-41, was able to kill cancerous cells, including breast cancer cells that do not have estrogen receptors, without killing healthy cells.

Estrogen and progesterone receptors and a receptor for a protein called HER2 are commonly found in breast cancer. These receptors are like “locks” that certain treatments, or “keys,” can open to kill the cancer cells. But roughly 10 to 15 per cent of all breast cancers are triple-negative breast cancer (TNBC), an aggressive form of the disease that is more likely to have already spread by the time it is discovered, according to the American Cancer Society. The “triple-negative” name derives from the fact that these cancer cells test negative for all three of the receptors, making it much more difficult to treat, with chemotherapy the primary option for most patients. Those who are under 40 and who are Black have the highest risk of developing TNBC, which also has the highest mortality rate among the different types of breast cancer.

“The ERX-41 compound did not kill healthy cells, but it wiped out tumor cells regardless of whether the cancer cells had estrogen receptors,” Dr. Jung-Mo Ahn, an associate professor of chemistry and biochemistry with the University of Texas at Dallas who synthesized the new molecule, said in a statement.

In fact, it killed the triple-negative breast cancer cells better than it killed the ER-positive cells.”

Ahn said he and his research team were puzzled by the results at first and did not know what the molecule could be targeting.

After several years of research chasing a number of dead ends, the scientists eventually determined that ERX-41 was binding to a cellular protein called lysosomal acid lipase A (LIPA).

“For a tumour cell to grow quickly, it has to produce a lot of proteins, and this creates stress on the endoplasmic reticulum,” Ahn explained.

“Cancer cells significantly overproduce LIPA, much more so than healthy cells. By binding to LIPA, ERX-41 jams the protein processing in the endoplasmic reticulum, which becomes bloated, leading to cell death.”

Endoplasmic reticulum (ER) is a network of sac-like structures and tubes in the gel-like cytoplasm within a cell. Proteins and other molecules move through this network.

“Using a variety of biochemical and ultrastructural studies, we have shown that ERX-41 induces ER stress,” the authors wrote in the paper, adding that the molecule shuts down a certain type of protein synthesis, blocks proliferation and causes apoptosis, or a type of cell death.

“Our results suggest that ERX-41 aggravates this already engaged system in TNBC to exhaust its protective features and cause apoptosis. In normal cells and tissues ERX-41 does not induce ER stress.”

The compound proved effective at killing cancer cells in human tissue taken from cancer patients, as well as in mice that carried human forms of cancerous tumours, with the tumours shrinking. No adverse effects were observed in the mice.

“Importantly, ERX-41 treatment did not show overt signs of toxicity, as evidenced by unchanged body weights of treated mice,” the authors wrote.

“Histologic evaluation following ERX-41 treatment showed no significant changes in gross histology of multiple organs including heart, lung, spleen, liver, kidney, uterus and pancreas.”

The molecule also appeared to work against other types of cancer that showed high levels of endoplasmic reticulum stress, according to researchers, including difficult-to-treat pancreatic and ovarian cancers, as well as glioblastoma, an aggressive and fast-growing brain tumour.

The authors said ERX-41 may be useful in treating patients with multiple solid tumours.

EtiraRX, a start-up co-founded by Ahn and co-authors Dr. Ganesh Raj, a professor of urology and pharmacology with the UT Southwestern Medical Center, and Dr. Ratna Vadlamudi, professor of obstetrics and gynecology at UT Health San Antonio, announced plans to begin clinical trials of ERX-41 as an oral drug as early as the first quarter of 2023.

“Triple-negative breast cancer is particularly insidious — it targets women at younger ages; it’s aggressive; and it’s treatment resistant. I’m really glad we’ve discovered something that has the potential to make a significant difference for these patients,” said Ahn.

https://www.ctvnews.ca/health/a-new-molecule-kills-hard-to-treat-cancers-in-tissue-samples-and-mice-study-shows-1.5941788