Addressing Cancer Therapy Resistance by Targeting Translational Regulation

Despite some significant recent innovations in therapeutic approaches to cancer, many patients across cancer types either do not respond to treatments or exhibit only a brief response before developing resistance, only transiently postponing the initiation of cycles of chemotherapy. Among the approaches being explored to overcome these challenges in the complexity and adaptability of cancers is targeting the regulation of translation, including pioneering the development of selective translation regulator inhibitors (STRIs), a new class of cancer therapies, by clinical-stage biopharma company eFFECTOR. In this Q&A, eFFECTOR’s President and Chief Executive Officer Steve Worland, Ph.D., explains the importance of the overlooked mechanism of translation and the potentially broad applicability of STRIs across cancers and beyond and discusses eFFECTOR’s plans for its two lead assets, tomivosertib and zotatifin, with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): To begin, can you introduce me to eFFECTOR and the company’s guiding mission and vision?

 Steve Worland (SW): The founding idea was simply to build on current treatments in cancer and do better for patients. There have been some remarkable breakthroughs in cancer therapy, but most patients still either don’t respond or develop resistance fairly quickly. Recently, there has really been a wealth of additional information and technology that is being brought to bear to address these challenges. eFFECTOR was founded to marry that new science with patient outcomes to allow patients to stay on well-tolerated regimens for as long as possible. We would love to turn cancer into a manageable chronic disease instead of a life-threatening sentence.

DA: I know that eFFECTOR is pursuing this important mission by exploring translation regulation, particularly pioneering the investigation of selective translation regulator inhibitors (STRIs). What inspired you to focus on these STRIs, and what do you see as the unique promise of this approach?

SW: At the inception of eFFECTOR, one of the key considerations was that, to extend the duration of benefit of a given treatment, you have to contend with resistance. It had become clear that, even when using the most tightly targeted therapy or immunotherapy, resistance happens. I’ve spent about 15 years in the antiviral world working with anti-infectives, mostly antivirals, and we experienced successes with both HIV and hepatitis C by really thinking hard about resistance and anticipating it ahead of time.

As eFFECTOR was getting off the ground, the information that was necessary to allow us to approach cancer that way was finally becoming available in the literature. As we learned more about resistance to several different types of therapy, we began looking for a type of therapy that would combat multiple aspects of resistance at the same time.

Our early work built on science done at the University of California, San Francisco, which had uncovered that the production of many proteins that confer resistance to different types of therapies was controlled by the process of translation. That was an important insight, because previously nearly all research had focused on transcription rather than translation. The UCSF group recognized that cancer hijacks the translation step, and that that hijacking can lead to resistance to a therapy. That realization suggested a new way to attack cancer by addressing that resistance, which was multifactorial within a tumor but had some commonalities from cancer type to cancer type. What really drew us to the STRI platform was this idea that, with a few examples, we could contend with resistance in multiple different tumor types.

DA: I’m curious about the platform technology that you use to investigate translational upregulation in different tumor types and so forth. Can you give us a peek under the hood of how you’re doing the discovery work?

SW: There are some fundamental challenges that we needed to overcome. If you want to see when translation is dysregulated and then be able to test whether you can fix that dysregulation, you need a way to measure translation, and you can’t just look at protein levels in a cell full of other compounding factors. At UCSF, they developed a technique to measure how many ribosomes were on a messenger RNA, which is highly predictive of the rate of protein synthesis. That’s really the fundamental step.

For the target, we had known for some time about the key components that control ribosome entry onto the messenger RNA. At least two of those were already known to be either oncogenes or controlled by tumor suppressors — so from a conceptual standpoint there was a big red arrow flashing at these targets. However, they were also known to be nearly impossible targets from the chemistry perspective. Many companies had even written articles suggesting that developers give up on attempting to drug these targets. We had some great medicinal chemists on the team who love a challenge, so we decided to drug these undruggable targets and deal with translation. It took the first five years of the company’s existence just to do the medicinal chemistry to invent the molecules that are now in the clinic.

DA: You are of course beginning with a small number of indications, but how generalizable do you imagine this approach will ultimately be across cancer types?

SW: I imagine it could be quite broad. The data are already leading us down multiple roads. It turns out that one of our targets is critical in T cells, as part of the adaptive immune response. One of the big breakthroughs in cancer about 10 years ago was immunotherapy, but it turns out that tumors are clever, and they develop resistance to these therapies.

Right now, we’re trialing the first drug in non-small cell lung cancer, which is kind of a great proving ground for immunotherapy. We think that if it works there — and we have good early data suggesting that it will — then it will be quite broadly applicable. Most tumors now have been addressed by some form of immunotherapy. If we can make immunotherapy better by delaying or preventing the emergence of resistance, we think that’s applicable across tumors and therapies. To take one example, I think that Merck has approvals for Keytruda in over 20 different tumor types.

Another major concept that we’re trialing in ER+ breast cancer is that these are essential proteins that control the cell cycle: cyclin D1, cyclin E, CDK4, and CDK6. Those are translationally regulated based on signaling that gets disrupted in cancer, and we are confident that targeting them will be quite broadly applicable.

There’s obviously lots of work ahead, but the short answer is that we believe our two lead assets will have very broad applicability.

DA: eFFECTOR is very much pioneering in this space, but given the data that you have generated so far and the response that you have received, do you think that translation regulation in cancer is due to become a lot more crowded soon?

SW: I think so. I think it’s always the case that when people see success in the clinic, other people think about either adjustments of the same compound with next-generation agents or alternate mechanisms. Right now, of course, we are hearing a lot about RNA, which, beyond the vaccines and things of that nature, presents another way to address translation.

I think we’re already seeing what will become a pretty broad effort in translation, which is interesting, because translation was all but ignored for 30 years. All the hot stuff was happening at the level of transcription — promoters, enhancers, super-enhancers — and most everyone viewed translation as merely a housekeeping function. But our founders, along with a small group of our investigators, discovered a second regulatory step at translation. Some of the most important proteins that have very profound effects on a cell have a second, failsafe mechanism at translation — and of course cancer exploits that to translate and make these proteins where they otherwise shouldn’t be made.

DA: It’s funny — I got a bunch of translation-associated hits in a genomic screen looking into DNA repair and checkpoints about 20 years back; at the time they were kind of dismissed as just weird and inexplicable, but now they probably make more sense.  

We mentioned your two lead candidates — can you give me an overview of those programs, the indications you are investigating, and where they are in their clinical journey?

SW: So, let me start with Tomi (tomivosertib) because that was the first to reach the clinic. As an example of the power of this technique that I mentioned, we were originally thinking of it as a tumor cell–intrinsic drug that will kill a tumor cell, and that’s true in some B cell lymphomas. But when we did an unbiased screen of what gets translationally regulated by our drug, we get all immunological leads — proteins like PD-1, TIM-3, and LAG-3, all of which are well characterized and the targets of drugs that are currently on the market or in clinical development. That made us realize that the drug’s primary effect is in activated T cells. What Tomi does is basically make the activated T cell last longer, to be a more effective killer of tumor cells for a longer duration.

We decided that the best way to trial that drug is to pair it with an already successful immunotherapy like a checkpoint inhibitor, such as PD-1 or PDL-1 inhibitor, and extend the benefit to those patients. Even among the patients with non-small cell lung cancer who do the best on checkpoint inhibitors, their median time to progression is only seven months. So, six months later, you’re back to figuring out what to do next, which is usually to start cycling through some chemotherapy.

Tomi is now in a randomized phase IIb trial. In phase IIa, we took patients who were not doing well on their checkpoint inhibitor — meaning that they had no response or that they had a response and then it failed — and we just added our drug. What we saw was that we could really re-establish the checkpoint inhibitor. The new regimen of Tomi on top of the failed checkpoint was successful in many patients.

We gave these patients another year. You start on the checkpoint therapy, and you progress. Then you add Tomi in a subset of patients, and they got another year on average before they progressed again. That’s pretty meaningful. That was a non-randomized trial, but now we’re in a placebo-controlled randomized phase IIb trial with data anticipated in the second half of this year. We are hoping to show that adding our drug Tomi on top of pembrolizumab extends the benefits that you see with pembrolizumab alone.

Our second candidate is zotatifin, which is an inhibitor that blocks translation of a different set of proteins — cyclins, cyclin-dependent kinases, and estrogen receptors. We have already publicly announced that we have seen some activity in ER+ breast cancer, some examples of confirmed responses where tumors shrink, with nice duration of benefit as well.

We have a presentation at ASCO soon detailing a larger data set with 18 patients evaluable for disease, where we’re using our drug zotatifin in combination with other agents. These are primarily patients who’ve already failed, so they’re looking at a pretty dismal set of choices going forward, cycling through a fairly ineffective hormone therapy followed by a not-particularly-effective chemotherapy. We want to jump in ahead of that and extend the benefit of a well-tolerated regimen and put off the time that patients need to start going through the different cycles of chemotherapy.

We are very excited about the initial data that we’ve seen. Even beyond that, I’ve been in the business a long time, and when the molecular story and the patient story and the genomics all start lining up, it usually means that you’re really onto something. Sometimes we still see drugs that work really well by mysterious mechanisms that no one understands at a molecular level, but that’s very uncommon recently.

Nowadays, when everything locks into place, you know what patients to enroll and you know that the molecular mechanism matches what you’re seeing in patients and in their tumor DNA and whatnot. As that becomes coherent, that’s usually a marker of success because you know what to do next instead of waving your hands and explaining away weird stuff. We have a very strong molecular link to the actual patient experience that we see, which is an excellent predictor of success.

DA: You were also exploring using zotatifin in COVID-19, correct?

SW: That program is no longer a focus for the company, but it was interesting work, and it was nice to be able to work on what was at the time the planet’s biggest problem. The rationale was that cancer upregulates the translation of proteins that need a particular protein called eIF4A, which is an RNA helicase. It turns out that COVID-19 needs that same protein, so it was a very natural extension to investigate whether an inhibitor of eIF4A could be an effective COVID therapy. Preclinically, we showed that it was super potent, and we did see a positive trend in a very small human cohort. I believe that zotatifin could absolutely be effective in COVID. COVID therapies have moved more into the public health setting now, and new drugs like that are not as needed as they might have been, which is actually a good thing. But should new variants emerge and overwhelm the existing therapies, I think we’d be in a position to make zotatifin available to try to address that.

DA: It definitely struck me that translation is potentially relevant to just about anything. Cancer is definitely the obvious place to start, but do you see other possible applications for your molecules?

SW: RNA viruses would be the next most obvious place because they bring in the RNA to make proteins but not the translation machinery — they hijack that from the host. If there were a clear next therapeutic area to go after cancer, it would certainly be RNA viruses: coronavirus and other examples. We’ve tested it fairly broadly, and it has been quite active against a number of different pretty nasty RNA viruses. If it becomes needed due to a public health outbreak, we can make it available.

DA: What longer-term plans do you have for these compounds as the success continues? Do you have a plan to commercialize them or are you looking for partners?

SW: Probably yes to both of those. As a small company sitting where we are today, we wouldn’t aspire to commercialize globally. But I think that everybody knows the dynamics in cancer therapy in the United States, and it doesn’t take that big of a sales force to be able to address the key centers for treatment in the community of oncologists. I began my career at a company working in HIV, and we just went ahead and did our basic science, did our clinical development, launched the drug, and went on to have a successful company. I thought that’s what you always did. And we will go down that path now, but this time we anticipate finding a partner to share the globe. It doesn’t make a lot of sense for us to build out the kind of infrastructure to commercialize outside of the United States.

I think the most efficient way for us to reach global markets would be to form very high-quality partnerships with one or more companies who have a similar mission to ours and who also see the products similarly. Ultimately, if you gauge the fastest way to get the drug to the patients — which is also, not surprisingly, the best way to reward the investors — then bringing in people to help spread the two indications as quickly and as geographically widely as we can makes a great deal of sense. And that, I think, would be the next step that we look to take from a partnership/licensing point of view.

It's never easy to predict whether someone will come in at the right point and make an offer that the board determines is ultimately the best for shareholders, leading to an acquisition. All of the paths forward are the same: develop the drugs as if you’re going to own them forever or they’re going to be owned by one of the top notch, global pharmaceutical companies; all those activities we do today are exactly the same on either path. We do everything with an eye that these drugs are going to launch, so all these background activities are done in parallel to the clinical activities. We’re ready for either of those two outcomes.

DA: I know that your focus is of course on these very promising candidates that you have in trials, but it seems like you’ve just opened the door to a broader STRI approach. How are you looking to expand your pipeline: other indications or combinations with these compounds or more discovery work?

SW: I think the most logical place for us to expand is to use these two existing agents and expand the potential indications there. In the first one, where we’re looking at non-small cell lung cancer right now: with success in that phase IIb trial, it would be very natural to move into a registration trial but also look at other tumor types that are known to respond to checkpoint therapy but don’t respond that well. There is a genetic class that has a high level of mutations called MSI High. There’s renal cancer (although that’s pretty well-addressed today), bladder cancer, endometrial cancer, and so on. I think that would be a very logical expansion of our pipeline into additional indications; the same thing for zotatifin.

The first wave of expansion would be to take it to existing agents and expand the number of indications that we’re looking at there. Beyond that, I think the expansion would actually then be indication-specific: are we becoming a lung cancer or a breast cancer company? In that case, we might as well look for something that was complementary — which wouldn’t necessarily be an STRI — to make for a coherent message addressing breast cancer doctors.

DA: Calling back to the vision that you discussed in the beginning: what impact do see your candidates having on oncology? Where do you see them fitting into the continuum of care for their targeted indications, in the near and longer terms?

SW: In lung cancer, we’re trialing in first-line treatment for metastatic disease. I think you want to get to the tumors as early as you can and prevent as much genetic complexity from developing in the tumor to prevent the tumor from shutting down the immune system. There is a natural spot for us to add our candidates right away as first-line therapy disease by disease. For the second agent, zotatifin, in the case of ER+ breast cancer, first-line treatment is fairly good. The median progression-free survival (PFS) for first-line metastatic disease is about 24 months now.

For the second line and beyond, the median PFS until you need to have chemotherapy for a lot of those metastatic cancers is on the order of a few months. Then you get chemo and you have the toxicity associated with chemo, and there is even a risk of death from the use of some of those agents. For breast cancer, I think the initial indication would be in the second line, after the first two years, on average, of relatively good experience. Eventually, I believe that it would add benefit in the first line and make those 24 months even longer, but, as you can imagine, if your benchmark is 24 months, then the next goal would be to show 30–36 months, and that’s quite a long trial.

So, it’ll take a while to get into first line. But that’s good for the patients; when it’s harder to show improvement in first-line therapy, it means that patients are doing pretty well on first-line therapy. You can really look disease by disease and understand how good first-line therapy is for each. If the best you can do is six or seven months, like lung cancer, you go first line and make it better. If you get 24 months in first line, then you’d probably look at second line.

DA: We’ve mostly focused on the science, but I wanted to see if there was anything you’d like to share about the team you’ve assembled at eFFECTOR and the culture and morale underlying this work?

SW: First and foremost, to be successful, you have to have a mission that people not only buy into but become very passionate about. We have quite a small team here: around 15 employees and a number of excellent consultants who help out in specific areas. Every one of them works as hard and as creatively as they do because of the importance of the mission. We like to take on challenging problems and figure out how to address them, in pursuit of the mission of improving patients’ outcomes. We’ve been very fortunate to attract a very strong team, not just in senior roles but across the entire company.           

We are small, and like any biotech we have to deal with financial pressures, but we have been able to attract a really talented team because people are very energized and motivated by the mission. Our mission to reach patients motivates people across the whole spectrum — every bit as much in finance as in R&D. The folks in finance follow the outcomes of the trial and know when the next datapoint is going to come out as well as people on the R&D team; and they’re as motivated to work at a biotech company trying to address cancer as everybody in R&D.

Steve Worland, Ph.D.

Dr. Steve Worland has served as President and Chief Executive Officer and as a member of the board of directors of eFFECTOR since its inception in May 2012. Previously, Dr. Worland served as Chief Executive Officer of Anadys Pharmaceuticals, Inc., a biopharmaceutical company, from August 2007 until its acquisition by Roche Holding AG in 2011. Dr. Worland was an NIH postdoctoral fellow in molecular biology at Harvard University and completed a Ph.D. in chemistry at the University of California, Berkeley. He received his B.S. with Highest Honors in biological chemistry from the University of Michigan.