Innovative Cancer-Fighting Gene Targeting Research



7mins | Article

Prof Mariano Barbacid, Permanent AXA Chair, aims to discover treatments for cancers with some of the lowest survival rates. In 1982, Prof Barbacid was among the first to discover the first human oncogene—a gene that can, under certain circumstances, transform a cell into a tumor cell. This led to the revelation that cancer is a genetic disease caused by mutations in key genes. Since being awarded the AXA Chair, he has continued to research the K-Ras oncogene, which is the most frequent mutation in lung, colorectal, and pancreatic cancers. Here, Prof Barbacid shares some of his recent innovative gene targeting research, as well as the welcome news that we are slowly but surely winning the fight against cancer, even if the enemies are complex.

Why is it so important to understand the underlying mutations of different cancers?

Each cancer type has to be understood individually according to its pathology, stage, metastatic status, and underlying mutations. For instance, K-Ras is mutated in 20% of human tumors, and is the most frequent mutation in three of the big killers: lung, colorectal and pancreatic cancer. Targeting K-Ras will be a major advance for the treatment of these tumors. In my laboratory, we work with lung and pancreatic cancer, for which K-Ras is the initiating mutation, so blocking K-Ras activity can be expected to have better therapeutic consequences than in tumor types for which K-Ras is not the initiating mutation, such as colorectal cancer.

Ironically, K-Ras was thought to be undruggable just 5 years ago, and chemotherapy has been the standard of care for K-Ras mutant tumors for the past 39 years. In June 2021, the FDA approved the first selective inhibitor against K-Ras, Sotorasib (Amgen). This is the beginning of an explosion of new drugs to treat this cancer type. Unfortunately, Sotorasib is only active against one of the different types of K-Ras oncogenes. Therefore, its use is limited to some types of lung cancer and to a lesser extent, colorectal cancer. Yet, K-Ras inhibitors against the other mutations are currently being generated in several pharma companies. Indeed, we are witnessing the beginning of an explosion of new drugs to treat those cancers induced by K-Ras oncogenes.

Could you describe some of your main findings?

We use genetic manipulation to first define what’s relevant. For this, we create genetically engineered mouse models by introducing mutations present in patients into mice DNA, which causes the growth of tumors that are similar to human tumors. Mouse tumors are smaller and have fewer mutations than human tumors, but are the closest experimental models we can work with. We use these mouse tumor models to identify therapeutically relevant targets. Our strategy is, conceptually, relatively simple. Once the mice have developed the corresponding tumors, we use molecular scissors to eliminate potential therapeutic targets, that is, targets whose elimination will cause the tumor to either stop growing, regress, or even disappear. Needless to say, those targets whose elimination have little or no effect on tumor growth are no longer considered.

In a mouse model of lung cancer, we found that elimination of one of the three direct downstream signaling targets of K-Ras, a protein named RAF1, resulted in the regression of almost two thirds of all tumors, including the complete elimination of about 10% of them. Hence, these studies have indicated that we should concentrate our future studies to selectively targeting RAF1. We have also carried our similar experiments with genetically engineered mouse models of pancreatic tumors. In this case, elimination of RAF1 did not produce any therapeutic benefit. However, when we combined RAF1 ablation with the elimination of a second target, the EGF Receptor, we observed the complete regression of these pancreatic tumors in about half of the mice. This is the first time anyone has reported the complete regression of pancreatic tumors.

How does this work facilitate the next stage of drug discovery?

Our mouse tumor models have allowed us to identify potential therapeutic targets. Other than K-Ras itself, our studies have shown that RAF1 is the most suitable target by which to block K-Ras mutant cancers.

Since RAF1 is a specific kind of enzyme known as a “kinase”, the pharma industry has developed kinase inhibitors—none of which have shown significant therapeutic activity. Last year, we provided a potential explanation for the failure of these inhibitors in the clinic. Unexpectedly, using our genetically engineered mouse tumor models, we discovered that RAF1 does not participate in tumor progression via its kinase activity. Hence, making RAF1 kinase inhibitors is useless for the treatment of K-Ras mutant tumors.

These observations have forced us to change our drug discovery strategy and we are now concentrating on eliminating RAF1 itself rather than blocking its kinase activity. To try to unveil the best strategy to degrade RAF1 we decided to determine its 3D structure using cryo-electron microcopy in collaboration with Dr. Guillermo Montoya, Head of the cryo-EM facility at the University of Copenhagen. The results of this collaboration have been recently reported in Molecular Cell. We have identified some “structural vulnerabilities” in RAF1 that will allow us to start a drug discovery program to find ways to destroy the RAF1 protein in human cancers.

How much closer do your findings bring us to new treatments for lung/pancreatic cancer?

Science doesn’t always generate immediate results, as with K-Ras oncogene—the first drug came almost 40 years after its discovery. The good news is that there have been many advances in the overall treatment of cancer, and every year there’s a breakthrough in one type of cancer. The fight against cancer is being won slowly but steadily.

Just 24 years ago, there were no targeted therapies, and cancer was treated with chemotherapies. In 1998, the first targeted product, Herceptin, was approved—a monoclonal antibody for the treatment of certain types of breast cancer. We now have targeted therapies for many different types of cancer. Still, the problem with precision medicine is that each target needs its own drugs. In just 20 years, pharmaceutical companies have used information generated by many translational research groups to develop selective drugs for more than two dozen oncogenes and their related products, thus providing useful and less toxic therapeutic options for many patients with cancer.

Likewise, immunotherapy, which is a therapy that inhibits the ability of tumors to suppress the immune response of the patient, was an experimental therapy only 10 years ago. Today, immunotherapy has become the best therapy for many cancer types since it doesn’t depend on specific mutations, so the same drugs are active against many different cancers. We can say without any doubt that the last 20 years have seen incredible advances for the treatment of many cancer types, which is resulting in increased rates of survival for most patients with cancer and significant improvements in their quality of life.

What’s next?

Cancer research is a marathon, not a sprint. I will continue working on K-Ras, since the discovery of its first inhibitor is just the tip of the iceberg. The approved drug, Sotorasib, is only active against one of the multiple K-Ras mutations, so there are still many things to do. I hope no one will confuse our commitment to K-Ras research with a lack of innovation—with 1 in 5 patients with cancer still dying from this mutation, continuing to work on inhibiting K-Ras mutant cancer is a top priority, and an unresolved medical need.

For instance, Sotorasib is not suitable for the treatment of pancreatic cancer. We also need to identify additional targets to expand the therapeutic opportunities for those tumors that did not respond to our previous approaches. In addition, it is essential to identify drugs that are capable of eliminating RAF1 from K-Ras mutant tumors. This is not an easy task, especially as it will require the involvement of the pharma industry. However, we can now draw the road map towards reaching this goal, based on our pioneering results on the structure of RAF1. In summary, there is still a lot of work ahead of us. Fortunately, the scientific community is generating exciting breakthroughs that suggest that targeting K-Ras mutant tumors could be a reality in a not-too-distant future.

October 2022