#01: Faeth Therapeutics

Faeth Therapeutics is on a mission to change how we think about cancer care, one meal at time.

By bringing precision nutrition to the frontlines, Faeth is taking an innovative, and potentially quite powerful, approach to the battle against cancer. Led by an all-star team of scientists and physicians, and a driven CEO, Faeth is building what may not only be the future of cancer care, but healthcare as well.

Together with evidence-based science, standard-of-care chemotherapy, and a product experience focused on the patient and their caregivers, Faeth is taking a holistic approach to fighting one of the deadliest diseases known to humankind.

Today, we'll dive into some of the history and science that led to the the creation of Faeth Therapeutics. We'll learn more about Faeth's founding team of scientists and innovators, how they're delivering precision nutrition to cancer patients, and an outlook on the future of the company.

The Warburg Effect

Otto Warburg, a German physiologist and biochemist, had begun to investigate the metabolism of cancerous tumor cells in the 1920's.

During his research, Warburg made the puzzling discovery that cancer cells consumed far more glucose than healthy cells. And not only were cancer cells devouring glucose, they were using it inefficiently.

Every cell in our body uses glucose, or sugar, for energy. When our cells consume glucose, they normally use it in a process called aerobic respiration, using oxygen to turn glucose into lots of ATP, the molecules that cells use for fuel.

But when there's not enough oxygen available, our cells switch to anaerobic respiration.

Anaerobic respiration is both less effective and less efficient at producing ATP, and results in a lot of waste products, most notably lactate. Warburg found that cancer cells, even in the presence of plenty of oxygen, still opted for anaerobic respiration to generate energy. This was confusing, because not only were the cancer cells consuming more sugar than healthy cells, they were using it wastefully.

The unique and confusing metabolism of cancer cells came to be known as "The Warburg Effect", and Otto Warburg was awarded the Nobel Prize in 1931 for discovering it. He would go on to hypothesize that, because of cancer cells insatiable appetite for sugar, if we could remove it from the diet, then we could stop cancer in its tracks.

But Warburg was never able to prove this. Decades passed, and around the 1980's, researchers turned their attention from cancer cell metabolism to cancer genomics, looking for genetic signatures of tumors that could be targeted with drugs. The idea that nutrition could be used in the treatment of cancer fell to the wayside, and cancer metabolism research halted.

Until recently.

Three Teams, One Discovery: Starving Cancer Is Possible

While Warburg's hypothesis that depriving cancer tumors of sugar alone could kill them was never proven, the idea that you could slow cancer growth by starving it of specific nutrients would.

Throughout the 2010's, three separate research teams would converge on this idea. Each would identify different nutrients and metabolic pathways that could be interfered with to starve specific cancer tumors. In combination with chemotherapy, this approach--pairing a precision nutrition diet with cancer drugs--would yield remarkable and promising results.

The scientists we're about to meet, and their incredible discoveries, would go on to found Faeth Therapeutics.

The Science Behind Faeth Therapeutics

The story of Faeth starts in the lab of Karen Vousden, PhD, at the CRUK Beatson Institute in Glasgow.

Vousden's lab had long been focused on understanding a gene known as p53 and its role in cancer. p53 is a tumor suppressor gene. When activated, it encodes a protein known as a transcription factor, which stops cells with damaged DNA that could go on to become cancerous from replicating. However, when this gene is mutated, it ceases to function normally. The protein it encodes can no longer do it's job, and cancer cells can grow unchecked.

In 2010, Oliver Maddocks had just finished a PhD in molecular biology, and joined Vousden's lab as a post-doc. Both researchers had a budding interest in cancer cell metabolism, and began looking at the nutrient demands of cells with p53 mutations.

Starting with cancer cells in a dish, the two scientists started experimenting. First, they looked at growth in cells with and without p53 mutations. The cells with mutations that turned off p53 grew rapidly, while those without mutations didn't. This was expected. Then, they began adding nutrients, starting with amino acids. If these cancer cells needed specific amino acids to grow, they would soon find out. And it turns out, they did. Maddocks noticed that after adding serine and glycine to the dish, two non-essential amino acids, the cancer cells that had initially failed to grow begin to proliferate.

This was an exciting discovery, because it meant that by restricting these amino acids, cancer growth could be halted. But the excitement was tempered. Neither Maddocks or Vousden thought this finding to be all that promising for human cancers. This was because these were non-essential amino acids, which our cells can make on their own. It didn't matter if you took them away from the cancer cells, they thought, because the human body could make them on their own.

Still, the two scientists suspended their doubt. In an article for Cancer Research UK, Maddocks said, "The way Karen and I thought about this was, let's assume we don't know the answer before we talk ourselves out of doing an experiment". They pressed on, deciding to conduct a study in mice with colorectal cancer. One group of mice would receive a standard diet, and the other would get a specially-formulated diet that lacked serine and glycine.

To their surprise, the mice that had been given the SG-free diet lived longer, despite the fact that they synthesize their own serine and glycine. The paper was published in the journal Nature in 2013, a landmark study in cancer metabolism.

Over the next few years, Maddocks and Vousden looked deeper, conducting more studies. They'd publish another paper in Nature in 2017, once again showing that mouse models of lymphoma and intestinal cancer could be starved by giving the mice a serine-glycine-free diet.

But the results weren't always so straightforward. In this same study, they gave mice with pancreatic cancer the SG-free diet, but found that the cancer was resistant. This was because the pancreatic cancer in these mice had a mutation that allowed it to turn up its ability to synthesize serine.

While this nuance in the study's findings may seem discouraging at first, it's important to note, as it will later help us understand Faeth's approach as a company. One thing that makes cancer so difficult to treat is that even in people with the same cancer, differences in mutations can mean the same treatment is more effective in one person than the other.

Simply put, every cancer is unique, and thus requires an equally unique approach to treatment.

The serine-glycine-free diet was certainly unique, and by 2017 Maddocks and Vousden were convinced that it could be translated into a treatment. But on its own, it wasn't obvious that this discovery would sew the seeds of a company.

That was until discoveries by two separate research teams, converging on the same idea that cancer could be starved, would change their minds.

While the success of any cancer treatment is predicated on slowing and shrinking tumor growth, the ability to stop it from spreading is equally, if not more, important.

Metastasis, or the spreading of cancer from its original site to other parts of the body, is what ultimately kills an estimated 90% cancer patients.

Many factors contribute to cancer metastasis, but one known factor in some cancers is the activity of an enzyme called asparagine synthetase (ASNS). This enzyme synthesizes asparagine, a non-essential amino acid. Asparagine appears to be an important regulator of cancer cell metabolism, making it a target for potential therapies.

Around 2017, Gregory Hannon's lab at the CRUK Cambridge Institute had been investigating what role asparagine may play in promoting metastasis. Together with Simon Knott, a scientist and professor at Cedars Sinai Medical Center of Los Angeles, Hannon's lab conducted a study that looked at a similar dietary intervention to the one Maddocks and Vousden had created, only this time removing asparagine from the diets of mice with breast cancer.

Published in 2018 Nature, the results showed that mice on the low-asparagine diet suffered significantly less metastasis compared to mice on the high-asparagine and control diet. Interestingly, the removal of asparagine from the diet didn't do much to slow the growth of the original tumor, it only reduced it's ability to spread.

Still, preventing metastasis was a huge win, and further bolstered the idea that nutrition could act as a true therapeutic in cancer care.

During this same year, another study would be published that would only further validate this idea, forming the final piece of the foundation that would lead to the creation of Faeth Therapeutics.

In the 1980's, a scientist named Lew Cantley had begun researching cancer cell metabolism, right around the same time most researchers had stopped.

During this time, Cantley and his team discovered a family of enzymes known as PIK3. Broadly, PIK3 plays two major roles in the life of a cell, when activated. It helps the cell consume glucose for energy, and it sends signals to the cell telling it grow. This activity is normal and healthy in non-cancerous cells. But in some cancers, PIK3 has been hijacked. Cantley's lab discovered that certain cancers have mutations in PIK3 that turn up its activity, amplifying the signal to both grow and eat sugar.

Another important discovery made a few years later, by Dr. Bert Vogelstein, an oncologist, was that PIK3 is activated by insulin, a hormone our bodies release to control blood sugar.

In the case of a normal, healthy cell, insulin and PIK3 work together to regulate blood sugar and cell metabolism. But when it comes to cancer cells, this can be a recipe for disaster. Many cancers have already hacked PIK3, turning up its activity, allowing it to consume more glucose than a healthy cell. Insulin only further enables this, acting as an accelerant for tumor growth.

The logical conclusion from this research was that if you wanted to slow cancer growth, you needed to block PIK3, cutting off a major fuel highway for cancer cells.

And that's exactly what drug companies tried to do.

PIK3 inhibitor drugs were developed, four of which are now FDA approved for use in specific cancers. But they have a counterproductive side effect. PIK3 inhibitors actually end up increasing insulin, since they cause sugar to stay in the blood for longer periods of time. Insulin, as you'll remember, activates PIK3, ultimately limiting the effect of the drug.

Cantley knew this, and had been thinking of ways to make PIK3 inhibitors more effective. One hypothesis was that if you could limit the release of insulin in patients on a PIK3 inhibitor, you could increase its efficacy.

At Cantley's lab at the Meyer Cancer Center at Cornell, he and a team of researchers, which included future co-founders of Faeth, conducted a study to test this hypothesis.

Using mice that had been implanted with human cancer tumors, the team set up three experimental groups. The control group received only a PIK3 inhibitor drug. Each of the three experimental groups received the same drug, plus an intervention designed to minimize their insulin response. The three insulin-minimizing interventions included two drugs, Metformin and an SGLT2 inhibitor, both of which lower blood sugar. The third intervention was a ketogenic diet, which is a high-fat, low-carbohydrate diet.

The results, published in Nature in 2018, showed that all three insulin-minimizing interventions made the PIK3 inhibitors more effective at slowing tumor growth. However, the most significant results came from the ketogenic diet group. Without sugar coming from the diet or insulin from the pancreas, the tumors became highly sensitive to the drug designed to block PIK3. This was a revelation, because it meant not only had the team figured out, in principle, how to make a proven chemotherapy more effective, but that it could be done through modifying diet alone.

At the start of the 2010's when Maddocks and Vousden conducted their first precision nutrition study, there were only a handful of researchers seriously looking at the intersection of cancer genomics, metabolism, and the role that nutrition plays in tumor growth and metastasis, and the effectiveness of chemotherapies.

But by 2019, this had changed. Maddocks and Vousden were aware of the studies that had come out of Gregory Hannon and Lew Cantley's labs, and this shared knowledge brought the three teams together. In unison, they decided that the best way to translate their findings from the lab to real cancer patients would be to start a company.

Thus in 2019, Faeth (which is the Welsh word for "nutrition") was born.

However, creating and testing the diets for real cancer patients would only be the first step. Getting the food to patients, helping them on their journey, and discovering new cancer-starving nutrient pathways would be an entirely new challenge, one they would tackle with the help investors, physicians, and a CEO.

The Faeth Team

Faeth was started by the eight scientific co-founders from the three research teams we met earlier, and would be joined by two more co-founders later on. Scott Lowe, PhD, the Chair of Cancer Biology & Genetics at Memorial Sloan Kettering would join as another scientific co-founder, and Anand Parikh would join as co-founder and CEO.

Today, Faeth has around 30 employees helping them on their mission to bring precision nutrition to cancer care, including registered dietitians, world-class chefs, product managers, and people in operations.

The Faeth Approach

Faeth is approaching cancer care from multiple fronts. The precision nutrition diets are, of course, the main approach. But to make these diets more effective, and to create additional therapeutic diets in the future, Faeth has developed their own machine learning discovery platform, called MetabOS, which scours known tumor genomes looking for weaknesses that can be exploited by diet-drug combinations. Faeth is also helping patients, both in the general population and those enrolled in clinical trials, stay on top of their care, learn about nutrition, and work with a Registered Dietitian through their mobile app.

Clinical Trials

The first, and necessary, step to the Faeth team realizing their vision is clinical validation.

Up to this point, all the research that points to precision nutrition as a weapon against cancer had been done in cells and mice. Clinical trials are needed to prove its efficacy in human cancer patients. Faeth currently has two clinical trials underway, with more in the pipeline being conducted in mouse and cell models. The first clinical trial is testing an insulin-suppressing diet in combination with a PIK3CA inhibitor, in patients with advanced clear cell ovarian, endometrial, and colorectal cancers. The second trial is testing a non-essential amino acid restricted (NEAAR) diet in patients with pancreatic cancer, who are also being treated with gemcitabine and nab-paclitaxel. Both trials target cancers that have been shown to be sensitive to diet modification in combination with chemotherapy.

If you or someone you know is interested in learning more about Faeth's ongoing clinical trials, you can learn more here.

Getting clinical validation is crucial for a number of reasons. First, it gives oncologists and their patients reliable evidence that precision nutrition works as a therapeutic in humans, which means it can actually be prescribed under the proper circumstances. It also makes Faeth's therapies reimbursable by insurance payers, driving down costs for patients and creating a revenue source for Faeth.

In fact, according to CEO Anand Parikh, even if some insurance payers end up not reimbursing patients for Faeth's meals, the company plans on giving the meals and app access away for free. This is because they believe it is the right thing to do, and will help precision nutrition, and nutrition education, reach as many cancer patients as possible. Costs also won’t be a concern, especially if Faeth can prove that their approach works well in humans, which would be a landmark development in cancer care and generate significant earnings for the company.

Current clinical trials are focused on very specific cancer types that have shown to be sensitive to nutrient depletion based on the tumor genome. But Faeth is also looking for more cancers they can target with precision nutrition and standard cancer therapies. To do this, they've developed their own machine learning platform, called MetabOS, which scours the genomes of tumors to find those that may be sensitive to restriction of certain nutrients.

Precision Nutrition Meals & Snacks

Rigorous scientific thought has gone into the development of Faeth's therapeutic diets, but so has culinary expertise.

Faeth's meals and snacks are crafted by world-class chefs, and are designed to not only starve tumors, but to provide patents with delicious and nourishing food. Located in Boulder, CO, Faeth's kitchen prepares the meals and then ships them directly to patients.

The meals are made specifically for the trial that the patient is enrolled in. For example, patients in the pancreatic cancer trial receive a diet that is restricted of certain non-essential amino acids, whereas patients in the trial for cancers that have a PIK3Ca mutation receive an insulin-suppressing diet. These diets would be difficult, if not impossible, for cancer patients to make on their own at home. Faeth makes it as easy as possible for patients to eat a diet that nourishes their healthy cells, while starving their cancer cells. Patients can choose from a variety of meals and snacks that meet their specific needs, and are not stuck with one rigid menu. Home meal delivery also helps with patient compliance, a crucial, but often overlooked aspect of healthcare.

Alongside customized meals, Faeth patients may also get specially tailored supplements and therapeutics based on their condition. These therapeutics are packaged and sent along with the meals, and include instructions for when and how to administer them.

The Faeth App

To support patients outside of the clinic, Faeth has developed an app for iOS and Android. The app is meant for use by clinical trial patients and their caregivers, but also provides value for anyone managing a cancer diagnosis for themselves or someone they care for.

I spoke with Burnett King, the Director of Product at Faeth, who gave me some insight into the vision for the Faeth app.

Faeth's product team is focused on creating a digital support system for cancer patients and their caregivers, by providing tools, education, and nutrition-focused guidance. Patients enrolled in a Faeth clinical trial receive tailored education around the trial they’re enrolled, the diet and medications they’ll be on, and the science behind Faeth’s treatments. Through the app, they’re also able to respond to surveys about their experience in the clinical trial.

Patients using the app, whether or not they're part of a clinical trial, also get access to a Registered Dietitian. The RD, or Faeth Coach, is there to answer questions about nutrition, provide guidance and support, and aid the participation of clinical trail patients. The Registered Dietitians on staff at Faeth all have an oncology-focus, and are a great resource for any cancer patient or caregiver who wants to lean more about nutrition in cancer care.

Also included in the app experience are care management tools, such as goals, to-do lists, and a calendar for keeping track of appointments, all helpful adjuncts in terms of patient compliance.

The app is a good place for any cancer patient to go to get guidance and support on nutrition, for free and on demand. It also serves as an avenue for clinical trial enrollment, which users can request information on through the app.

Taken altogether, Faeth's approach combines precision nutrition meals, specially formulated therapeutics, and a digital experience, forming what can truly be considered a modern and holistic healthcare experience.

Funding

To date, Faeth has been backed by some high profile venture capital funds and investors.

In June of 2022, they closed a $47-million Series A round led by SG2 Ventures, money that they are putting towards advancing clinical trials. Their previous seed round was co-led by Khosla Ventures and Future Ventures, putting their current total funding $67 million.

Other firms that have been involved in funding Faeth include Digitalis, KdT Ventures, AgFunder, and Cantos.

Looking Ahead

The future is bright for Faeth, but potentially even brighter for cancer patients.

Early evidence from Faeth's clinical trials is showing promising results, with more potential cancers in the pipeline.

It will take several more years to know the true impact of precision nutrition on cancer outcomes in humans. It takes time to build up enough scientific evidence for new treatments to take hold, especially for a disease as devastating and perplexing as cancer. Faeth is leading the way toward a future where nutrition will be the fifth pillar of cancer care, alongside radiotherapy, chemotherapy, surgery, and immunotherapy.

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