Tag Archives: Pancreatic

New compound shows promise against hard-to-kill pancreatic and breast cancers, in mice

A drug developed at the Georgia State University (GSU) could pave the way towards new treatment avenues for pancreatic and breast cancer, according to a pair of reports.

Image credits Miguel Á. Padriñán.

The drug, christened ProAgio, was developed by Zhi-Ren Liu, a biology professor at the GSU, and his team. Lab tests with mice showed that the compound is effective at treating pancreatic cancer. A second study shows that it is also effective against “triple-negative breast cancer”, a particularly aggressive and hard-to-treat type of breast cancer that had poor treatment prospects up to now.

Taking down the walls

The drug works by targeting not the disease’s cancerous cells themselves, but rather the ones they use for defense. Cancer cells use fibroblasts, a specialized type of cell that produces collagen and other mechanically-strong molecules, to build a shield around the tumor. This shield is called “stroma” and acts as a physical barrier preventing drugs from reaching inside and doing their job.

ProAgio targets these cells and forces them to undergo apoptosis — programmed cell death. This breaks down the stroma, leaving the tumor vulnerable.

According to the authors, it’s this stroma that makes pancreatic cancer extremely lethal and difficult to treat. The 5-year survival rate for this type of cancer is only 8%, they explain. Triple-negative breast cancer also tends to form a very dense stroma, and offers similarly poor prospects for patients. The team hopes that targeting these conditions’ most powerful asset and neutralizing it would finally give our current cancer treatments the upper hand.

“All solid tumors use cancer-associated fibroblasts, but in pancreatic cancer and triple-negative breast cancer, the stroma is so dense there’s often no way for conventional drugs to penetrate it and effectively treat the cancer,” said Liu.

Furthermore, the stroma is also involved in the tumor’s ability to confuse our immune systems. So it not only insulates from direct treatment but also makes immunotherapy — which uses our natural immune systems to fight cancer — much less effective.

Since cancer-associated fibroblasts also grow new blood vessels to supply the tumor, they speed up its spread through the body. Any cells that break off from the tumor can enter the bloodstream and start developing somewhere else, which we call metastasis. ProAgio, the team showed, has a pronounced effect on the vasculature of tumors. For pancreatic cancers, it helped reopen healthy vessels that were crushed by the stroma. For triple-negative breast cancer, it reduced the rate of new blood vessels being created by the tumor.

ProAgio is derived from a human protein and targets a specific receptor on the surface of cancer-associated fibroblasts to make sure it doesn’t attack any other, healthy tissues.

“When you have a wound, for example, normal fibroblasts will secrete fibers to limit the damage and promote healing,” said Liu. “The tumor region is basically a wound that won’t heal. Quiescent fibroblasts may play a role in preventing cancer from spreading. You don’t want to kill the good guys, only the bad guys.”

The drug is currently licensed to ProDa BioTech, a pharmaceutical research company founded by Liu. It has currently passed the toxicology and pharmacokinetic studies required before a drug can enter the first stages of clinical trials. These will start after ProAgio passes its Investigational New Drug (IND) Application, the process through which the Food and Drug Administration gives its approval for testing with human subjects.

The first trials will likely begin in early 2021 if everything goes well with the FDA, Liu says, and hopefully everything will progress to late-stage trials sometime by the end of the year.

The first paper “Simultaneously targeting cancer-associated fibroblasts and angiogenic vessel as a treatment for TNBC” has been published in the Journal of Experimental Medicine.

The second paper “Modulation of Cancer-Associated Fibrotic Stroma by An Integrin αvβ3 Targeting Protein for Pancreatic Cancer Treatment” has been published in the journal Cellular and Molecular Gastroenterology and Hepatology.

Pancreas adenocarcinoma.

This one gene seems to underpin pancreatic cancers in mice

Turning off one gene could completely block pancreatic cancer.

Pancreas adenocarcinoma.

Pancreas adenocarcinoma.
Image credits Ed Uthman / Flickr.

Pancreatic cells work in some pretty hazardous conditions. So, they come equipped with a particular gene that allows them to switch back to a more ‘primitive’ state and divide to make up for any fallen colleagues. However, this process can also create the conditions for pancreatic cancers to develop — and one group of researchers is looking into how to prevent it from happening. The results far exceeded their expectations.

Under maintenance

“We found that deleting the ATDC gene in pancreatic cells resulted in one of the most profound blocks of tumor formation ever observed in a well-known mice model engineered to develop pancreatic ductal adenocarcinoma, or PDA, which faithfully mimics the human disease,” says corresponding author Diane Simeone, MD, director of the Pancreatic Cancer Center of NYU Langone Health’s Perlmutter Cancer Center.

“We thought the deletion would slow cancer growth, not completely prevent it.”

The study built on the theory that pancreatic cancers develop when adult cells switch back to high-growth cell types (acinar-to-ductal metaplasia or ADM) — like those that drive fetal development — to repair local tissues. If this reversion takes place in the presence of genetic errors, the repair process quickly goes haywire, leading to unchecked cellular proliferation — cancer.

Led by researchers from the NYU School of Medicine and the University of Michigan, Ann Arbor, the team found that the ATDC gene must be active for injured pancreatic cells to undergo reversion. They focused on a type of pancreatic cells called acinar cells. Acinar cells produce enzymes to support digestion and dump them in the small intestine via a network of ducts.

But, they don’t call them digestive enzymes for nothing — these compounds do damage the ducts and associated cells as they move towards the small intestine. It’s not particularly heavy damage, but it does build up over time. As such, acinar cells have evolved to easily switch back into stem-like cell types, as did pancreatic duct cells, in order to heal this damage. If they do undergo this repair process after acquiring random DNA changes (mutations), however, they are prone to becoming cancerous. Mutations of a gene called KRAS, for example, have previously been linked to aggressive growth in more than 90% of pancreatic cancers, the team explains.

The team artificially caused pancreatitis in mice by treating them with cerulein, a signaling protein fragment that damages pancreatic tissue. ATDC gene expression (i.e. activation) did not increase right after the damage was caused. Rather, it took a few days to get going, which the team says is consistent with the timeframe required for acinar cells to reprogram genetically into their ductal cell forebears. Mutant KRAS and other genetic abnormalities induced aggressive pancreatic cancer in 100% of the mice used in the study — if the ATDC gene was present and active.

However, none of the mice used in the study developed pancreatic cancer in the absence of an active ATDC gene. Further experimentation has shown that ATDC gene expression triggers beta-catenin, a cell-signaling protein that activates another gene, SOX9. Previous research has linked SOX9 to the development of ductal stem cells and to the aggressive growth seen in PDA. The present study supports this link, finding that cells lacking ATDC can’t become cancerous due to their inability to induce SOX9 expression.

In human tissue, the team reports based on a study of 12 human pancreatic tissue samples, ATDC expression seems to be more pronounced than that seen in mice. Its activation increased further during the transition of ADM into human pancreatic ductal adenocarcinoma. The findings could help serve as a base for developing new prevention and treatment strategies for pancreatic cancer, the team concludes.

The paper “ATDC induces an invasive switch in KRAS-induced pancreatic tumorigenesis” has been published in the journal Genes & Development.

Ancistrocladus heyneanus.

Rainforest plant may treat pancreatic cancer through ‘antiausterity’ properties

The discovery of a new plant may spell doom for pancreatic cancers everywhere.

Ancistrocladus heyneanus.

Ancistrocladus heyneanus, a close relative of the plant described in this study.
Image credits Vinayaraj / Wikimedia.

Congo’s rainforests may end up curing pancreatic cancer. New research reveals that a vine native to these forests (Ancistrocladus likoko) can dramatically decrease cancerous cells’ survivability, paving the way to new treatments against the disease.

Anti-austerity measures

“The promising antiproliferative and antimetastatic activities of the new alkaloid presented in this paper suggested [it could] be a rewarding candidate for further studies regarding its anticancer potential against human pancreatic cancer,” the paper reads.

Pancreatic cancer is one of the most dangerous, deadly forms this disease can take. Survival rates at the 5-year mark are below 5%. One of the deadliest traits of the disease is that cancerous pancreatic cells spread around extremely aggressively, hogging up all the oxygen and nutrients available around the tumor.

In these conditions, most cells would find it impossible to survive — and, indeed, healthy pancreatic cells quickly start dying. However, pancreatic cancer cells manage to survive, even thrive, under such conditions. This trait, known as ‘austerity’, is perhaps the single most important reason why pancreatic cancer is so deadly and difficult to root out.

Pancreatic cancer cells’ austerity draws on a cell signaling pathway called Akt/mTOR. Finding a compound that can throw a wrench into the Akt/mTOR — so-called ‘antiausterity’ compounds — is a key goal of researchers and doctors in the fight against pancreatic cancer.

Now, an international team of researchers reports finding a new and promising antiausterity alkaloid compound in the Ancistrocladus likoko vine deep in the Congolese rainforest. The team has previously discovered alkaloid compounds with antiausterity potential in other vines in the region, and the present research was spurred by that work.

Cancer antiausterity test.

Ancistrolikokine E3 suppressing the migration of pancreatic cancer cells in a wound-healing assay carried over 48 h. The effect is concentration-dependent, the team explains.
Image credits Suresh Awale et al., 2018, JoNP.

For the study, the team extracted chemical compounds from ground twigs of the vine and separated them using high-performance liquid chromatography. They then analyzed and documented the 3D structure of the new alkaloid — which they christened ancistrolikokine E3.

The alkaloid, the authors report, can successfully inhibit the Akt/mTOR pathway. This effectively allows it to kill pancreatic cancer cells pressed by nutrient starvation, but not when nutrients were plentiful. Ancistrolikokine E3 also inhibited the migration and colonization of cancer cells in mice during lab tests, suggesting that it could also be helpful in staving off metastasis in human patients. The new alkaloid is thus a promising compound for anticancer drug development based on the anti-austerity strategy, the team concludes.

The paper “Ancistrolikokine E3, a 5,8′-Coupled Naphthylisoquinoline Alkaloid, Eliminates the Tolerance of Cancer Cells to Nutrition Starvation by Inhibition of the Akt/mTOR/Autophagy Signaling Pathway” has been published in the Journal of Natural Products.