There is real hope that the tragically low survival rates from pancreatic cancer could be improved in the coming years.
There are more than 500,000 new diagnoses of pancreatic cancer each year worldwide[i]. Sadly, survival rates from the disease are still low with figures from the U.S. National Cancer Institute showing a five-year survival rate of 12.8%[ii]. In Europe in 2020, pancreatic cancer was responsible for almost 29% of all cancer-related deaths [iii]. It is the seventh most common type of cancer in Europe, but the fourth leading cause of cancer-related deaths, behind lung, colorectal, and breast cancers. By 2030, it is widely predicted to become the second most common cause of cancer mortality of 90% [iv]. Furthermore, there is a rise in pancreatic cancer cases, especially in young people [v].
There are several reasons for the low survival rate; pancreatic cancer is often diagnosed late, it is likely to be aggressive by the time it is detected and it is liable to spread to other parts of the body.
There is also a lack of screening despite worldwide statistics showing that it is the 12th most common cancer[i] and pancreatic cancer is difficult to remove surgically as it’s often buried deep between blood vessels and other organs.
Once diagnosed, pancreatic cancer is sometimes difficult to reach with drugs too, because of the physical barriers that surround it. It is often associated with fibrosis (scar tissue) that prevents the immune system and drug from penetrating and attacking the tumor.
As scientific advances continue, immunotherapy drugs are becoming a standard of care choice for this cancer, however the fibrosis can also act as a barrier to the T-cell infiltration. Efforts are being made to alter the tumor microenvironment to favor immune cell activity and combat tumors. This includes targeting immune-suppressive cells and modifying the extracellular matrix that contains the fibrotic tissue.
Fibrosis significantly impacts tumor progression, immune evasion, and treatment resistance, with tumor-associated fibroblasts (TAFs) playing a key role by secreting growth factors and components of the extracellular matrix.
Recent research has focused on modulating the connective tissue surrounding cancer known as stroma and fibroblasts to enhance pancreatic cancer treatment efficacy.
In October, international fibrosis experts convened in Barcelona (Spain) , to discuss advancements in targeting pancreatic cancer via the autotaxin (ATX) pathway.
Recent research has focused on modulating the stroma and fibroblasts to enhance pancreatic cancer treatment efficacy.
The presence of ATX is a “stress signal” indicating hypoxic conditions surrounding the tumor and the presence of a feedback reaction, whereby cancer cell proliferation is boosted while immune responses from tumor targeting T-cells are suppressed.
At the conference, experts led a discussion centered on the autotaxin mechanism in fibrosis, its relevance to pancreatic cancer, as well as its relevance to other fibrotic tumor types.
There are multiple reasons to target autotaxin to modify the tumor microenvironment. Research shows that it inhibits cancer cell growth and fibrotic processes, while stimulating the immune effector cells.
Davide Melisi (University of Verona, Italy) noted:
“With all cancers, drug resistance is an important consideration, and there is the potential to combine agents from redundant pathways such as TGF-beta. Fibrosis is implicated in several other cancers, and we could use the anti-fibrosis approach to treat other diseases such as breast and gastrointestinal cancers”
First discovered in the early nineties, ATX inhibitors work by preventing the action of the enzyme, which converts the precursor lysophosphatidylcholine (LPC) into a signalling molecule known as lysophosphatidic acid (LPA), which can induce various responses along multiple cellular signalling pathways.
iOnctura has the only ATX inhibitor in oncology clinical development – cambritaxestat, which is in Phase I development for pancreatic ductal adenocarcinoma (PDAC).
Interestingly, parallel translational research has shown pancreatic cancer resistance mechanisms are mostly stroma-driven and are not mediated by KRAS amplification or new KRAS mutations, as described in other tumor types such as NSCLC.
With a growing understanding of targeting tumour-cell specific pathways and pathways enriched in the pancreatic tumour stroma, novel combinations with iOnctura´s ATX inhibitor cambritaxestat are being explored.
On this World Awareness Day for Pancreatic Cancer, today, like every other day we continue to pursue small molecules for big impact in cancers which continue to evade treatment.
With these new research insights, there is real hope that the tragically low survival rates from pancreatic cancer could be improved in the coming years.
Our journey continues.
[i] https://www.wcrf.org/cancer-trends/pancreatic-cancer-statistics/
[ii] https://seer.cancer.gov/statfacts/html/pancreas.html
[iii] https://pmc.ncbi.nlm.nih.gov/articles/PMC10377815/
[iv] https://www.scientificamerican.com/article/why-pancreatic-cancer-is-on-the-rise/
[v] https://www.thelancet.com/journals/langas/article/PIIS2468-1253(23)00366-7/fulltext
