Breaking barriers in pancreatic cancer

World Pancreatic Cancer Day takes place on 21 November to raise awareness about pancreatic cancer, support patients and their families, and advocate for increased research and early detection of this deadly disease. iOnctura’s Chief Medical Officer Michael Lahn discusses how we can fight the disease by breaking the defensive wall surrounding these tumours. Pancreatic cancer is relatively common, yet survival rates are still low with figures from the US National Cancer Institute showing a five year survival rate of 12.8%1. In Europe in 2020, pancreatic cancer was responsible for almost 29% of all cancer-related deaths.2 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%.3 Furthermore, there is a rise in pancreatic cancer cases, especially in young people.4 There are several reasons for the low survival rate: pancreatic cancer is often diagnosed late, is likely to be aggressive by the time it is detected and 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 cancer5, 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 tumour. 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 tumour microenvironment to favour immune cell activity and combat tumours. This includes targeting immune-suppressive cells and modifying the extracellular matrix that contains the fibrotic tissue. Autotaxin in fibrosis Fibrosis significantly impacts tumour progression, immune evasion, and treatment resistance, with tumour-associated fibroblasts (TAFs) playing a key role by secreting growth factors and components of the extracellular matrix creating a microenvironment known as stroma. In October 2024, international fibrosis experts convened in Barcelona to discuss advancements in targeting pancreatic cancer via the autotaxin (ATX) pathway. Latest research has focused on modulating the stroma and TAF to enhance pancreatic cancer treatment efficacy. The presence of ATX is a “stress signal” indicating hypoxic conditions surrounding the tumour and the presence of a feedback reaction, whereby cancer cell proliferation is boosted while immune responses from tumour targeting T-cells are suppressed. An expert discussion took place, centred on the autotaxin mechanism in fibrosis, its relevance to pancreatic cancer, as well as its relevance to other fibrotic tumour types. Davide Melisi (University of Verona, Italy) explained that there are multiple reasons to target autotaxin to modify the tumour microenvironment known as stroma. Research shows that inhibiting autotaxin slows cancer cell growth and reduces fibrotic processes, while stimulating the immune effector cells. Melisi also noted that with all cancers, drug resistance is an important consideration, and there is the potential to combine agents from redundant pathways such as TGF-beta. He added that 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 blocking 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, which promote tumour growth. iOnctura has the only ATX inhibitor in clinical development for a cancer indication. Cambritaxestat, which is in Phase I development for pancreatic ductal adenocarcinoma (PDAC), is an oral drug and currently being combined with standard chemotherapy. While investigations continue to explore alternative treatment options in pancreatic cancer, the evidence is mounting that modifying the tumour microenvironment could be the key to improving outcomes for pancreatic cancer patients. For example, improving intra-tumour immune cell composition may result in better survival. Recent data from the Phase II trial of pancreatic cancer vaccine CAN-2409 indicated a median overall survival of 28.8 months for patients treated with the vaccine compared to 12.5 months in the control group.6 This suggests that the intratumourally delivered vaccine could shift the immunological balance favourably against pancreatic cancer in resectable early-stage pancreatic cancer. Blocking CD39 Another approach is to block the enzyme CD39 with the antibody TTX-030 to reduce the immune suppressive adenosine. This antibody showed a 30% objective response rate and a median overall survival of 19.1 months in a Phase I study in patients with metastatic pancreatic cancer.7 TTX-030 is currently being evaluated as first-line treatment for metastatic pancreatic adenocarcinoma in the global Phase II ELTIVATE trial (NCT06119217) that is randomising approximately 180 patients into three study arms: TTX-030 and chemotherapy (gemcitabine and nab-paclitaxel); TTX-030 plus anti-PD1 antibody budigalimab and chemotherapy; or chemotherapy alone.8 Pancreatic cancer could also be tested for the presence of genetic mutations such as PARP and KRAS, opening up the possibility of personalised therapies. KRAS occurs in 90% of pancreatic tumours and early trials of KRAS G12C inhibitor drugs like adagrasib and sotorasib have shown some promise.9 Recent studies in mice demonstrated that combining chemotherapy with the experimental KRAS inhibitor MRTX1133 significantly reduced tumour growth compared to either treatment alone. This drug, which targets the KRASG12D mutation which is implicated in over 42% of pancreatic cancer patients, was developed by Mirati Therapeutics, a company acquired by BMS in 2024.10 Revolution Medicines is progressing with its pan-KRAS inhibitor RMC-6236. The drug entered Phase III in November 2024 once Phase I data were presented early 2024. Concurrently, Pfizer is exploring the pan-KRAS inhibitor PF-07934040, a sign of an expanding interest in KRAS-targeted strategies. As KRAS inhibitors move forward in clinical development, parallel translational research has revealed that pancreatic cancer resistance mechanisms are mostly stroma-driven and are not mediated by KRAS amplification or new KRAS mutations alone. 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.11 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. Biography Dr Michael Lahn is the Chief Medical Officer of iOnctura. He joined iOnctura as Chief Medical Officer in 2019 after 20 years of industry experience at Eli Lilly and Company, AstraZeneca and Incyte Corporation. In his career, Lahn contributed to the development of several new molecular entities, such as small molecule inhibitors (including the ALK5 inhibitor galunisertib and the registration of osimertinib in NSCLC), large molecules, antisense oligonucleotides and vaccines. He is passionate about developing novel therapies in cancer and mentoring colleagues in clinical drug development. References https://seer.cancer.gov/statfacts/html/pancreas.html https://pmc.ncbi.nlm.nih.gov/articles/PMC10377815/ https://www.scientificamerican.com/article/why-pancreatic-cancer-is-on-the-rise/ https://www.thelancet.com/journals/langas/article/PIIS2468-1253(23)00366-7/fulltext https://www.wcrf.org/cancer-trends/pancreatic-cancer-statistics/ https://www.cancernetwork.com/view/fda-grants-ftd-to-can-2409-combo-for-pancreatic-ductal-adenocarcinoma https://clinicaltrials.gov/study/NCT06119217?termNCT06119217&rank1 NCT06119217 https://tcr.amegroups.org/article/view/25051/19607 https://www.cancer.gov/news-events/cancer-currents-blog/2024/pancreatic-cancer-kras-inhibitors-chemotherapy https://www.nature.com/articles/emm2017255