What role can autotaxin play in cancer therapy?
In some cancers scar tissue forms around tumours and forms a barrier that prevents drugs and immune cells accessing the tumor. This can make the cancer hard-to-treat using standard chemotherapeutic options. There is an increasing focus to determine whether drugs can be used to counteract the fibrotic process. iOnctura’s Head of Research, Giusy di Conza explains the Company’s plans to bring the first autotaxin inhibitor to patients with cancer.
Q.
What is the role of autotaxin in cancer?
Autotaxin (ATX) converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a signalling molecule that can induce various cellular responses along multiple cellular signalling pathways that leads to a build-up of fibroblasts. CAFs (cancer-associated fibroblasts) are the main source of autotaxin within the tumor microenvironment (TME). Autoaxin-LPA act in a paracrine way on cancer cells and promotes their proliferation. In addition, autotaxin-LPA also directly inhibits T-cell migration into the tumor bed. The overall impact is an immune-deserted, suppressive and therapy-resistant TME.
Inhibition of autotaxin is a novel treatment strategy that offers a three-pronged attack on the tumor through direct cancer cell inhibition, immune effector stimulation and inhibition of fibrotic processes, giving drugs and immune cells better access to the tumor.
Q.
What is the development strategy for iOnctura’s autotaxin inhibitor?
Translational research has demonstrated the potential of our autotaxin inhibitor cambritaxestat in multiple cancer models, including pancreatic cancer. This research has been published in the ESMO journal Immuno-Oncology and Technology (IOTECH), Cancer Research, the Journal of Experimental & Clinical Cancer Research, and Cancers. Across all these publications, cambritaxestat showed strong reduction of metastasis and tumor outgrowth in preclinical models, as well as safe and tolerable dosing in healthy volunteers.
Our research found that LPA levels are high in pancreatic cancer patients, and using cambritaxestat to reduce these LPAs has shown promising results in preclinical models. This preclinical research led us to start a Phase I study to investigate cambritaxestat in combination with standard-of-care chemotherapy. This study is ongoing.
Our research found that LPA levels are high in pancreatic cancer patients, and using cambritaxestat to reduce these LPAs has shown promising results in preclinical models.
Q.
What challenges have been encountered with early generations of autotaxin inhibitors tried outside oncology? How will cambritaxestat improve on this?
The early generations of autotaxin inhibitors resulted in substantial toxicity, as seen with the combination of ziritaxestat with pirfenidone and nintedanib in IPF. Cambritaxestat has excellent potency and specificity and distinctively inhibits both the catalytic and the chaperone activities of the enzyme. iOnctura’s data from cambritaxestat are encouraging on the safety front, as no toxicity was observed in healthy volunteer studies.
Q.
What other potential applications are being explored for cambritaxestat?
There are a number of other cancer indications we are investigating preclinically. We also recently uncovered a new mechanism of action for autotaxin in resistance to TGF‐β pathway inhibition. This opens up an exciting possibility of combining cambritaxestat with our preclinical TGF- β pathway inhibitor IOA-359 in different disease settings.
