The potential of drug repurposing: Laura Soucek and co-authors consider the case of kinase inhibitor ibrutinib

Recently published in the journal Oncoscience, Laura Soucek, Principal Investigator of VHIO´s Mouse Models of Cancer Therapies Group, and two of her lab members, Daniel Massó-Vallés and Toni Jauset, have co-authored an editorial on the repurposing of ibrutinib, a small-molecule Bruton’s tyrosine kinase (BTK) inhibitor for the potential treatment of a variety of different tumor types – either as monotherapy or in combination with standard therapies or immune-based strategies.

Over recent years, cancer researchers have been increasingly seeking out new applications for available and previously approved anticancer therapies for the treatment of additional tumor types. Teaching anticancer agents new tricks – so-called ´drug repurposing´, is now showing great promise and, importantly, since these agents have already been approved, they are more rapidly fit for purpose than their novel, experimental counterparts.

“The main advantage of drug repurposing is that these approved anti-cancer medicines with proven low toxicity can more rapidly transition to clinical trials for the potential treatment of other malignancies. Further, drug repurposing greatly reduces the high financial costs associated with the development of new medicines”, observes Laura Soucek.

Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) which is traditionally used to put the brakes on cancer cell growth for several blood cancers such as chronic lymphocytic leukemia due to its essential role in the maturation of B cells (B lymphocytes) implicated in some hematological cancers. In addition to B lymphocytes, BTK is also expressed in many other cell lines, which has led many research teams to explore the therapeutic effect of BTK inhibition on other types of cells.

Back in April 2015, Laura´s group published a study* in Cancer Research evidencing the mast cell-inhibiting properties of ibrutinib in mouse models with pancreatic ductal adenocarcinoma; the most common and aggressive of pancreatic cancers exhibiting significant mast-cell infiltration and rapid cancer growth and metastatic spread. Their findings showed that ibrutinib has an unexpected, potent anti-fibrotic effect which, when combined with standard chemotherapy, extends the survival of mice.

Since both the safety and the efficacy of this agent in the clinic have been previously established and approved for certain tumor types, these results, along with those of other groups, led to the fast-track initiation of a phase II/III clinical trial to validate the use of ibrutinib, in combination with standard chemotherapy, for the treatment of pancreatic cancer. Patients were subsequently enrolled from several clinical sites throughout America, Asia, and Europe, including the Vall d´Hebron University Hospital (HUVH).

“This is just the start in terms of therapeutic switching for ibrutinib”, comments Daniel Massó-Vallés, co-author of the Oncoscience editorial, Graduate Student of Laura´s group, and first author of the group´s 2015 Cancer Research paper.

“Emerging data from various mouse models of cancer also suggest that BTK inhibition in other cell types using ibrutinib can be extended beyond pancreatic cancer for the effective treatment of a spectrum of other solid tumors including breast cancer, melanoma, and colon cancer. Moreover, given that ibrutinib is capable of inhibiting other kinases in addition to BTK, its effect could be extended to other non-BTK-related cancers such as non-small cell lung cancer or HER2-positive breast cancer”, he continues.

Collectively these results suggest that ibrutinib could be a viable and more effective therapy against various solid tumors, either as monotherapy or, more likely, in combination with standard therapy or novel immune-based approaches. Pending outcomes from several current trials, upon successful validation, will ultimately represent a turning point from proof-of-concept into clinical reality for the subsequent treatment of a variety of solid tumors including melanoma, prostate, lung, and pancreatic cancers.

“As we eagerly await these results, we can certainly celebrate the case of ibrutinib in identifying new uses for existing drugs that may well in turn lead to proven therapeutic avenues for other malignancies such as solid tumors or other fibrotic diseases”, concludes Toni Jauset, also a Graduate Student of Laura´s group.

Reference:* Massó-Vallés D, Jauset T, Serrano E, Sodir NM, Pedersen K, Affara NI, Whitfield JR, Beaulieu ME, Evan GI, Elias L, Arribas J, Soucek L. Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Cancer Res.75(8):1675-81.

Photo: Laura Soucek, Principal Investigator of VHIO´s Mouse Models of Cancer Therapies Group