"Nothing is undruggable!" was the bold claim at the European Society of Medical Oncology Targeted Anticancer Therapies Virtual Congress 2021 the (ESMO-TAT).
Susan Bates, director of translational medicine at Columbia University Medical Center and session co-chair, described a role for the inhibition of protein translation in making that hope a reality.
There are some approved drugs that target the borders of protein translation – PI3K, for example, plays roles upstream of translation initiation, and mTOR senses nutrient status and growth decisions. But overall, Bates told the audience, protein translation is an "untapped therapeutic target" for cancer drugs.
Protein translation can be initiated via two distinct mechanisms. After transcription, mRNAs are modified for translation, including through the addition of a "cap" that serves as a signal to the ribosome. But many housekeeping genes are transcribed through cap-independent translation, through so-called internal ribosome entry site (IRES) translation. Targeting cap-dependent translation is thus a way to narrow down the proteins being targeted, and enriching for oncoproteins.
Bates highlighted the potential of eukaryotic initiation factor 4A (eIF4A), which is part of a three-protein complex that is critical for starting up the cap-dependent translation of mRNAs.
Zotatifin (eFT-226; Effector Therapeutics) is an eIF4A inhibitor that is in a phase I/II trial against solid tumors driven by HER2, ERBB3, FGFR1, FGFR2 or KRAS.
Structurally speaking, zotatifin is derived from rocaglate, a substance found in Mahogany trees. At the ESMO TAT meeting, Bates highlighted another class of eIF4A inhibitors, the pateamine A analogues.
Like rocaglate, pateamine A is a natural product – this one found in sea sponges – and like rocaglate, it prevents eIF4A from being able to unwind RNA in preparation for translation. Interestingly, a paper that is scheduled for publication in the April 15, 2021, issue of Cell Chemical Biology and is now available online reported that despite being structurally completed unrelated, rocaglate and pateamine A bound to their targets in an almost identical fashion, though what differences there were provided an explanation for why pateamine A analogues can target a broader range of RNA substrates than rocaglate analogues.
In preclinical experiments, the pateamine analogues DMPatA and MZ-735 were able to inhibit the growth of Myc-driven tumors. They also showed what Bates termed "remarkable" synergy with the histone deacetylase (HDAC) inhibitor romidepsin.
Myc is an oncoprotein that is altered in a large number of solid tumors. It is also activated by KRAS, and KRAS mutations are present in 90% of pancreatic tumors, which are Bates' clinical focus and remain among the most stubbornly refractory of tumor types.
Broad versus narrow
Bates acknowledged that targeting protein translation can seem like a tall order because it is an essential need for healthy as well as tumor cells. But there are other well-established targets, such as microtubules, that have very broad functions but also a viable therapeutic window for chemotherapeutic agents such as Taxol (paclitaxel) and other taxanes, and vinca alkaloids such as vincristine.
While part of the raison d'etre of targeted therapies is to offer an alternative to the toxicity of chemotherapies, Bates noted that the discontinuation rate of targeted therapies, an indicator of is almost twice the rate of cytotoxic therapies.
And translation inhibition may be have broader effects than other targeted therapies in an area where that is highly desirable. Because it does not target KRAS itself, zotatifin, for example, is not limited to a single mutation. While KRAS inhibitors adirasib (Mirati Therapeutics) and sotorasib (Amgen) are specifically indicated for patients with a specific amino acid substitution, the G12C mutation, patients with any activating mutation in KRAS, or with activating mutations, amplifications or fusions in the receptor tyrosine kinases HER2, ERBB3, FGFR1 or FGFR2 are eligible to enroll in the zotatifin trial.