Prime Regulator proteins control cancer transcription identity

Thousands of different genetic mutations have been linked to cancer, but a new study of nearly 10,000 patients, regardless of where the cancer originated, found that tumors could be stratified into just 112 subtypes and, within each subtype, the major regulatory proteins controlling cancer had an almost identical transcription state, independent of each patient’s specific genetic mutations.

The study, published Jan. 11 in Cell, confirms that Master Regulators provide the molecular logic that integrates the effects of many different and specific mutations to patients to activate a specific tumor subtype transcription state, and thus significantly expand the fraction of patients who may respond to the same treatment.

In particular, instead of looking for drugs that target mutated genes associated with increasingly smaller subsets of patients, the new study suggests that a much larger proportion of patients responded to novel drug classes designed to focus on Master Regulator proteins.

The new study of thousands of tumors from all types of cancers found that the major genetic programs necessary for the survival of cancer cells are mechanically controlled with just 24 Prime Controller models – so-called MR-Blocks – each with just a few of their kind. of proteins working together.

The analysis, which has the potential to streamline and improve cancer treatment in the future, was led by Andrea Califano, Dr., Cory Abate-Shen, PhD, and Mariano Alverez, PhD, at Columbia University Vagelos College of Physicians and Surgeons and Herbert Irving Comprehensive Cancer Center.

“In today’s personal medicine, we try to find out which one out of thousands of possible genetic mutations or, even worse, mutational patterns disease can trigger a person, and then hopefully we have drugs that can target the activity of the associated proteins, ”says Califano, Clyde Professor and Helen Wu in Chemical Biology and Systems and chair of systems biology at Columbia Vagelos University College of Physicians and Surgeons. ”But instead of wanting drugs that target all different mutations, our study suggests that we may just need to a few dozen different drugs that can target MR-Blocks, “he adds.

“By identifying the fullness of MR-Blocks that are active in each individual’s cancer it will guide us in selecting the most appropriate drug or drug combination for their treatment,” Califano says. This idea has already been tested in several clinical trials, including breast cancer, pancreatic cancer, and neuroendocrine tumors, as well as in the Columbia Precision Oncology Initiative, a large-scale, value-focused program genomic, immunotherapeutic, evaluation and Master Regulator-based therapies in 3,000 patients across eight invasive tumor types.

The benefits of personalized treatment are just too small for cancer patients

Most cancer patients receive the same treatment, which has been proven on thousands and thousands of patients. When these options fail, however, patients can opt for a personalized approach, which involves the identification of genetic mutations in the patient’s tumor to guide drug selection that is target these mutations.

But very few patients benefit from this approach, Califano says, because most tumors do not have drug mutations and often a few do not. there is no response or redistribution immediately after the initial response. “Relying solely on identifying genetic mutations to guide personalized treatment has not been the slam-dunk we all hoped for. Large studies have shown that only up to 5% to 10 % of patients benefit and the majority of patients eventually progress to a drug-resistant form of the tumor.So there is a great need for procedures that more, “he explains. “For example, targeting the BRAF oncogene with inhibitors such as vemurafinib provides a remarkable short-term response in melanoma patients with mutations in this gene. But relapse occurs alongside within a few months, so little will be seen of the overall survival benefit. “

Califano and his colleagues have focused on a different approach to personal therapy. Using advanced mathematical and physics-based methods to model complex biological systems, such as the molecular interactions that apply the biological logic of the cell, Califano and his team extracting data from thousands of cancer samples to understand how genetic mutations affect the activity of all the proteins in a malignant cell. Of course, genes are important only because they represent the plan for making proteins, and the latter are the molecules that are responsible for specific functions in the cell, including cell conversion. normal to tumor.

“If you model the cell as a complex electronic circuit, it will be easy for you to identify the specific parts where the abstract signals arising from mutated genes eventually come together,” he said. he says. “Instead of the individual mutations, these components represent the most universal vulnerability of the cancer cell.”

Many of these aggregation points are proteins that ultimately determine the position of the cell, even though they are rarely affected by mutations.

Califano calls these proteins, which are both essential and sufficient for the maintenance of cancer cells across almost all cancers, “Prime Regulators.” “You can think of Prime Regulators as the narrow opening at the base funnel, “he says.” The top of the funnel gathers the effects of all the relevant genetic mutations in the cell and ‘cannibals’ them into that narrow opening.

“We think it will be more efficient and effective to just plug the end of the funnel, by targeting one or more Prime Controllers, than to focus on all the proteins that feed into it. “

Key control blocks

Although primary rulers have been identified in several specific cancers, the new study for Primary Controllers looked at over 20 different types of cancer, as well as any potential transplants across multiple cancers.

To achieve this goal, the Califano team developed a computational device called Multi-Omics Master-Regulator Analysis (MOMA) to study gene expression and gene changes in tumors. They used MOMA to analyze 9,738 print samples from the Cancer Genome Atlas repository of the National Cancer Institute.

The analysis identified 407 Prime Controllers across the various cancers and found that these are organized into just 24 specific and interconnected models, or Key Controllers Blocks (MR-Blocks). In each MR-Block there are only a few key regulators working together to control the specific symptoms of cancer cell behavior. For example, MR-Block: 2, the most frequently activated block in the most invasive cancers, contains 14 cell growth regulators, DNA repair, cell division, and cell proliferation. The activity of this block was found as a predictor of adverse outcomes in many types of cancer. In contrast, MR-Block: 24 was found to be associated with inflammatory and immune response programs and was therefore a predictor of good outcome in melanoma.

On average, between two and six MR-Blocks were applied to each tumor.

Focusing on MR-Blocks as a treatment

The Califano team also showed that MR-Blocks activity in cell lines could be drug-modeled, positively influencing cell behavior in several types of cancer.

Targeting MR-Blocks, rather than individual sleep proteins, promises to prevent cancer cells from developing resistance, as individual MR-Blocks capture the effects of a very large number of potential leaks in their upstream routes, which would certainly lead to drug resistance. .

“We’ve shown that if you’re aiming for MR-Blocks, it’s really hard for the cell to go around the barrier,” Califano says. “The cell had to reprogram itself, which is something a cell doesn’t like to do and usually, although true with some exceptions, in fact, that leads to cell death. . “

Califano expects each patient’s cancer to be disinfected into its specific MR-Blocks and treated with drugs designed to target them, alone or in combination. The good news is that tumors need to passively execute many genetic programs in order to survive. So even targeting just one of several MR-Blocks tends to promote cancer cell proliferation, Califano says.

Unfortunately, even though the technology is there to easily identify which MR-Blocks are active in cancer patients, there are few if drugs developed specifically to target them. As a result, the Califano laboratory developed algorithms to assess the potential of existing drugs to inhibit or activate individual MR blocks. For example, the study shows that there are already four FDA-approved drugs that are capable of activating MR-Block: 14 in prostate cancer, thus significantly reducing the cell’s ability to migrate and metastasize. Drugs specifically designed to target Prime Regulators should be better than existing drugs, Califano says. As a result, a number of collaborations are underway to begin developing this new class of protectors despite the fact that, until recently, Prime Governors were considered proteins “to -accessibly ”.

“This is a new concept, so there hasn’t been much development of drugs like that,” Califano says. “But we are already testing drug candidates, and initial testing in both preclinical and clinical studies has exceeded our expectations.”