Despite the progress, there is still a long way to go to create genetic profiles of cancer tumors
Cancer genetic testing has come a long way since it first entered clinical use in 1995. Mutations in two genes, marked by the codes BRCA1 and BRCA2, then provided the first clues that it is necessary to take into account the decisive role of genetics when deciding on the ways of healing. It turned out that women who carry one of these two mutations (and have a family history of breast or ovarian cancer) are much more likely than the general population to develop breast or ovarian tumors. Since then, some of these women prefer to have their breasts and ovaries removed as a preventive measure before malignant tumors appear in their bodies.
In the years that have passed since then, researchers have come to the realization that most types of cancer are mainly due to faulty genes. For this reason, genetic analysis of cancerous tumors has become a standard procedure in many malignant diseases, such as breast cancer, lung cancer and colon cancer, since the information obtained can help in the way of treatment. Doctors have amassed a modest selection of drugs that can neutralize some of the most common mutations.
And yet, many patients have come to know that their cancer is due to mutations for which there is no cure. In fact, the role that many of these genetic changes play in the development of cancer is not understood. Complex analyzes of DNA made in a wide range of cancer types revealed a rich variety of mutations. However, very little of this encyclopedic information helps doctors make treatment decisions. To date, the US Food and Drug Administration (FDA) has approved only 29 tests for certain mutations that can directly affect treatment.
Several large research projects are now investing great efforts to identify additional mutations that could be used as drug targets, and to gather the information that will allow doctors to better assign patients to the most appropriate treatments. In early 2016, President Barack Obama announced National Cancer Research Project, similar to the project to send a man to the moon, with funding of one billion dollars that will include such genetic studies. However, the task is so broad and complex that it seems that the gap between genetic knowledge and the patient's well-being is expected to widen for a period of time, before the promised revolution becomes a realistic treatment for most cancer patients. "We are in a period of transition," he says Steven Channock, Director of the Cancer Epidemiology and Genetics Division at the US National Cancer Institute.
Drivers vs. passengers
The genetic changes that ultimately trigger the development of cancer can be classified into two main groups. One, mutations that originate in cells The germ rows and are inherited from the parents. the second, somatic mutations which appear during a person's life as a result of advancing age, smoking cigarettes or other environmental influences. Although hereditary changes in DNA often lead to violent malignant tumors, including some cancers that appear in childhood, such mutations in the germ lines are usually rare. The vast majority of human cancers result from somatic mutations.
Most somatic mutations are harmless. The body itself even corrects many of them in the quality control processes of the cells. But some manage to cause considerable damage because they cause cells to multiply uncontrollably. Many genes contain code for creating proteins that do most of the chemical work in cells. In the case of cancer, the harmful mutations tend to change the way certain proteins work in one of two ways: either they actively encourage excessive cell division, or they fail in their intended role of inhibiting cell division.
Researchers compare these genetic disruptions to drivers and passengers. The disruptions related to the proliferation of cancer cells and their survival are considered to be leading mutations (drivers), while the other changes are considered to be secondary mutations (passengers) because they do not seem to be important for the development of cancer and only "catch a ride on it". No one knows how many lead mutations are required to trigger each of the different types of cancer. One study determined that the development of an average cancer requires at least two leading mutations and at most eight. Other studies have found that cancer often has 20 leading mutations.
Early successes
Despite the difficulties in finding which genetic mutations are important for the development of a certain cancer, researchers began to make progress in locating mutations unique to cancer in the late 90s. Among the first treatments were the drugs: Imatinib mesylate (its commercial name Gleebak), which affects the common leader mutation of Chronic myeloid leukemia, AndTrastuzumab (its commercial nameHerceptin) that acts on the mutation in the HER2 gene responsible for about a quarter of breast cancer cases. More adapted treatments soon appeared.
In the last three years, lung cancer patients have been routinely tested for disruptions in the gene marked ALK. In about 7% of these patients, a genetic error that causes the fusion of the ALK gene with another gene creates an abnormal protein that drives the development of cancer. Drugs that block the mutant protein are more effective than standard chemotherapy in slowing the progression of the disease. The drug does not benefit patients with normal ALK genes.
Routine genetic testing has also helped patients with this type of skin cancer Melanoma. About half of melanoma patients have a mutation in the BRAF gene involved in the spread of cancer from the tumor site to other parts of the body. In 2011, the US Food and Drug Administration (FDA) approved the first drug that inhibits the activity of the mutant BRAF protein. In a new study, it was found that nearly 80 patients with metastatic melanoma who responded to the new drug lived an average of two years after treatment, a much longer period of time than the average of 5.3 months of life typical of patients whose skin cancer developed metastases. And sometimes, a unique mutation allows the doctor to avoid prescribing certain drugs. For example, certain types of colon cancer, which result from mutations in the KRAS gene or the NRAS gene, usually do not respond to certain drugs.
But several obstacles prevent further progress. It is not enough to find a genetic disruption in the cancer tumor. The impairment must be directly related to cancer growth and survival. Also, a reliable test must be developed to detect the mutation and a treatment that can take advantage of this mutation must be found. It turns out that it is very difficult to meet these requirements. It is not enough to find the mutations that cause cancer. Researchers also need to know which mutations tend to act at later stages. As the tumor develops, new mutations appear in it. At each such stage, one has to differentiate again between the leading mutations and the accompanying mutations. Then, if one drug stops working, a subsequent genetic test can direct doctors to the next option.
Creating drugs that will block leading mutations is not a simple task either. It is true that many disordered proteins, which are created as a result of a wrong code of somatic mutations, are located on the surface of the cancer cells and are within the reach of the drugs. But others are buried deep within the cells. To reach them, the drugs must be made of small enough molecules to infiltrate into the cell, but then they are usually too small and unable to attach to their target proteins. This difficult problem has left most of the common carrier mutations, such as p53, RAS and MYC out of the battlefield.
In addition to this, the drugs that did manage to reach the somatic mutations often only led to a minimal extension of the survival time. And even if a single drug targeting a particular driver mutation succeeds in shrinking a tumor, but leaves behind even one resistant cell, it can quickly multiply and create additional new tumors that do not respond to the drug. It is therefore possible that the treatment of certain types of cancer requires the treatment of several drugs together, as is done in the treatment of HIV. And yet, every additional drug carries with it its own cost and unique side effects. Researchers must therefore understand the optimal strategies in each treatment.
Many somatic mutations are quite rare, a problem that also slows down the transition from the laboratory to the clinic. Some mutations appear in less than XNUMX percent of patients with a certain type of cancer. A clinical trial is needed to assess whether a drug can target that mutation, but the task of finding enough patients willing and able to participate in such a study could take a long time.
New directions
All these challenges spur the development of new research methods, drug design, and the establishment of infrastructures to accelerate the expansion of precision genetic medicine. These approaches bring a new perception into account. Traditionally, cancer was defined by the location in the body where it first appeared, for example, in the breast or lung. But it turned out that certain mutations known to trigger a certain type of malignant growth in one part of the body are sometimes involved in cancers that normally occur elsewhere in the body.
Defining cancer not only according to its location in the body but also according to its genes paves the way for a treatment freed from the limitations of the past. There is a possibility that a drug that is accepted in the treatment of a certain type of cancer can also work in the treatment of another cancer caused by the same genetic disorder. When the drugs Trastuzumab (Herceptin) andLapatinib, which were approved for the treatment of breast cancer carrying a mutation in the HER2 gene, were given to a group of patients with late-stage colon cancer, for example, almost half of them survived a full year, a time considered unusually long. Although such links are still rare and preliminary, they suggest that it may be time to reconsider the standard definitions of cancer.
The National Cancer Institute (NCI) launched one of the new collaborations, MATCH, August 2015. This study is expected to involve 840 volunteers and is designed to provide the data doctors need to prescribe drugs to more patients based on the genetics of the tumors. The study will sequence the DNA of more than 5,000 cancer samples to find disruptions that may be suitable for gene-targeting drugs. When the trial began, eligible patients received one of ten combinations of gene-targeting drugs; The number of combinations has now increased to 24. Meanwhile, the American Cancer Society has allocated a seed sum of two million dollars for the two-year project, called GENIUS, which will collect both cancer DNA profiles and medical results of treatments for thousands of patients at seven major cancer treatment centers in the US and Europe. This database should provide information that will be used by researchers for many purposes, including identifying additional mutations that can be used as a target for targeted drugs and finding markers that can help diagnose cancer and rank the stage it is in.
These and other projects bode well for future improvements in genetically tailored treatment for cancer patients. However, today they are haunted by doubts about the length of time it will take them to lead meaningful changes. Also, the push for targeted drugs could weaken if drug companies turn their efforts toward other promising approaches, such as immunotherapy. Currently, the gap between the promise of personalized medicine and the reality remains frustratingly wide.
