Fertilizers extracted from fungi that grow on the roots of a flowering plant in Morocco show promise as a powerful antagonist of invasive triple breast cancer, scientists say.
There is early evidence that the peptide EnnA, isolated from a fungus that lives happily by a flowering plant known for its penchant of catching flies, directly inhibits the natural and powerful cell defender HSP90, which cancer clears to help avoid an attack by the immune system.
EnnA allows the defense system to do its job by getting HSP90 out of the way. We’re really excited about how this fertilizer affects tumors. “
Dr. Ahmed Chadli, Biochemist, Department of Medicine and Georgia Cancer Center at the College of Medicine Georgia at Augusta University
Chadli has received a $ 1.8 million grant (1 R01 CA249178-01A1) from the National Cancer Institute to further pursue EnnA ‘s potential.
Heat shock proteins such as HSP90 are molecular protectors, natural responders that help cells survive stress, withstand literally high temperatures as well as other injuries. Excessive pressure causes proteins to begin to open and lose their normal function, and when molecular chaperones cannot help proteins be folded back into shape, the proteins should be reduced and eliminated.
Cancer, with its many complex mutations and proteins, clears molecular chaperones, such as HSP90, to protect their “oncoproteins” and to survive the wild growth that is a sign of cancer. Additional cancers use the transmitted HSP90 as “checkpoints” on the surface of its cells to help them avoid attacking the drivers of the immune response called T cells.
Conventional HSP90 inhibitors have shown promise but have not been delivered as an effective cancer treatment with tolerable side effects. In fact, the normal defenders can improve cancer survival, Chadli says, by destroying the sexual ability of the cells to commit suicide when they are abnormally immature. This important cancer survival strategy remains a logical target that Chadli is looking for new ways to prevent.
What he did not intend to find was just an HSP90 inhibitor that also acts as a protective agent, a drug that activates, strengthens or restores normal immune function, so that T cells can see the their target.
Both the fungus Fusarium tricinctum and the plant Aristolochia paucinervis which is already considered to have medicinal benefits, and Chadli has evidence in both cell culture and an animal model of invasive, triple-negative breast cancer, that the compound EnnA is the result of their close relationship in the mountains of North Africa is the kind of effective tumor killer he has been looking for.
When Chadli looks at microscopic images of the breast cancer tumor 15 to 20 days after treatment with EnnA, for example, the normally dense breast mass is full of holes and a number of immune cells have invaded. “The immune system begins to recognize the cancer cells as foreign and goes and destroys them,” he says, a mechanism of tumor killing scientists calls “immunogenic cell death.”
“We’ve found that cells killed by EnnA appear to be vaccinated against subsequent cancer cell invasion,” Chadli says. In fact, tumors cannot infect mice vaccinated with these dead cells, he says.
“One of the interesting things about T cells is that once they are trained to attack a target, like triple-negative breast cancer, they attack it when it appears. at this on EnnA ‘s activity in terms of the powerful T cell response, “he adds.
HSP90 normally resides within cells and finds that EnnA brings it to the surface of breast cancer cells and also enables proteins, such as calreticulum, which normally secrete stay inside the endoplasmic reticulum of the cell, to the surface as well, where it resembles those “threat molecules” that call immune cells “come to eat me,” Chadli says. EnnA also triggers a special type of cell self-consumption called mitophagy in which the cell powerhouses, or mitochondria, eat them, an action that is also common in drugs that stimulate the immune system to function .
With the new donation, Chadli and his team are looking further into how EnnA ‘s inhibition of HSP90 leads to lower levels of the protective protein PD-L1, which helps protect some normal cells from being a target of T cells. Cancer cells have even higher levels of PD-L1 and other immune checkers attach to it to release this brake on the immune system, according to the NCI .
They also combine EnnA with an established treatment center that inhibits CTLA-4, a protein receptor on T cells and another natural immune checkpoint that cancer uses to keep itself out of the line of fire. Some conventional immunosuppressants block CTLA-4, according to the NCI, and Chadli combines these protectors with EnnA and then describes the immune cells that are appearing in response.
So far, Chadli and his team have not found any obvious side effects from EnnA, but that is something they are investigating further, along with any toxic, as well as identifying the best dose. with the idea of moving towards use in patients.
He also suspects, and has little evidence, that the fertilizer may be more widely applicable to other types of breast cancer as well as other types of solid tumors such as melanoma.
HSP90 protectors are not currently FDA approved. Side effects associated with immune systems under study include liver, kidney and eye damage as well as more classic symptoms of cancer treatment such as nausea and vomiting. Some existing protectors may block the efficacy of other drugs that may be used in combination with them, such as chemotherapy, which causes cell suicide, or apoptosis, and the defenders could suppress it.
Chadli identified EnnA as a novel inhibitor after attending a Moroccan Pharmaceutical Society Meeting a few years ago, where he met Dr. Abdessamad Debbab, a pharmacological chemist at the Institute for Pharmaceutical Biology- medicine and Biotechnology at Heinrich-Heine-University Düsseldorf. The two scientists began a collaboration that led to high-throughput screening of natural products from medical plants and organisms to identify HSP90 inhibitors that may not have had the first-generation fertility side effects. of defenders.
The plant Aristolochia paucinervis (Aristolochiaceae) begins to flower in February, and its flowers have a strong scent that attracts flies that are trapped inside by shoots that fly over night and the flies appear next. pollen-covered day. The root is used to treat a wide variety of GI problems, aortic palpitations and is an antidote for snakebite. The fungus Fusarium tricinctum has previously shown some potential against breast and cervical cancer due to its antiproliferative and antioxidant effects.
Tri-negative breast cancer does not respond to hormonal treatment, it is usually considered more aggressive and deadly than other breast cancers and there are currently no targeted treatments for this cancer, which makes up 10-20% of breast cancers. It is more likely to occur in women under the age of 50 and Black and Hispanic women are considered to be at greater risk, according to Breastcancer.org.
Source:
Georgia Medical College at Augusta University