This is a recurring column on clinical research in the early stages of development, which is referred to as phase one. These are treatments being used for the first time in a small number of human patients to determine safety, dosing and general pharmacological activity.

Despite scientific advances, certain cancers have eluded treatment for decades. Buoyed by recent regulatory successes, biotech companies have begun to take aim at these so-called "undruggable" targets in early-stage clinical trials.

The May 2021 U.S. approval of Amgen Inc.'s Lumakras, the first drug to target tumors with mutations of the KRAS gene, demonstrated that pathways to treatment once thought to be closed off due to biological constraints can potentially be opened.

"We achieved something that had eluded cancer researchers for over 40 years, offering new hope to patients with KRAS G12C-mutated cancers," Amgen CEO Robert Bradway said on a Feb. 8 investor call. "It's not a coincidence that we're seeing these decades-old challenges being solved at this particular moment in time — we're entering an extraordinary new era in biotechnology."

Targeted cancer treatments often zero in on a tumor's proteins, and the most successful targets have identifiable sites for a drug to connect with. For some prevalent proteins, like the one associated with the KRAS gene in non-small cell lung cancer, researchers had previously been unable to identify these sites.

But new advanced imaging technologies used by some smaller biotechs have widened the range of cancer targets that are potentially treatable, offering the possibility of a new generation of therapies.

Clearing a path

In some cases, the solution has been to find another spot along a mutated gene's signaling pathway, which allows a tumor to flourish. For example, the beta-catenin protein that exists on several tumor types has long been thought to be undruggable due to toxicity, but Houston-based Iterion Therapeutics Inc.'s candidate tegavivint targets another part of the protein's pathway, called WNT, to get around the problem.

"Beta-catenin is on that shortlist of coveted undruggable targets, up there with KRAS, where you know they're associated with a number of cancers but they've just been very challenging from a drug discovery development perspective," Iterion CEO Rahul Aras told S&P Global Market Intelligence.

"Finding those intelligent combinations where the pathway is active, where you may be able to find synergy with other treatments, is going to be important," Aras said.

Iterion has completed a phase 1 trial of tegavivint in patients with desmoid tumors, which are cancers of the connective tissue that are driven primarily by the pathway that the drug is designed to block, Aras said. The biotech has also begun early-stage studies in patients with acute myeloid leukemia, pediatric cancers and non-small cell lung cancer.

"Especially when you're looking at targets like the WNT pathway that's active in almost every cancer, there's a significant amount of effort that needs to be put into selecting where you have the highest probability of having an impact and being able to demonstrate that a drug is effective," Aras said.

The cancer field is ripe for a wave of innovation in targeted treatments, particularly as these pathways are better understood, the CEO said.

"I continue to hear a lot of optimism for what 2022 has in store, and there's going to be significant investor enthusiasm because we are at this tipping point in biotech where we're evolving at a rate I don't think we have before," Aras said.

The body's own tools

Salarius Pharmaceuticals Inc., another Houston biotech, has focused on targeted protein degradation, which is a way to flag previously undruggable cancer-promoting proteins to the attention of the body's own defenses so they can break the tumors down.

The company acquired a drug candidate called SP-3164 from DeuteRx LLC in January for approximately $2.5 million up front. SP-3164 is a type of "molecular glue" that can bring together the targeted protein and an enzyme called a ligase to signal to the body that the tumor should be destroyed.

The simplicity of this mode of action could open up more opportunities to address previously undruggable targets, Salarius CEO David Arthur told Market Intelligence.

"The beauty of molecular glues is by sticking to the protein that you're targeting, you use the body's own degradation and natural elimination processes to get rid of the cancer-causing protein that might have once been undruggable," Arthur said. "The ability to target that glue is the elegance of what turns out to be a very straightforward solution."

The blockbuster sales garnered by Revlimid, a first-generation molecular glue developed by Celgene and now owned by Bristol Myers Squibb Co., validates the commercial opportunity of the next generations of these types of drugs, the CEO said.

Along with pharmaceutical giant Bristol Myers, smaller U.S. biotechs like C4 Therapeutics Inc. and Foghorn Therapeutics Inc. are also moving into the space. "A number of companies are realizing how this approach can begin to develop treatments, either for patients that don't currently have them or improve the treatments that are currently available," Arthur said.