When Smart Medicine is Used?

In cancer treatment, smart drugs, also referred to as targeted therapies by doctors, are being used in more and more patients each year. Classic chemotherapy drugs affected many regions in both cancerous and healthy cells. These drugs damaged the genetic structure (DNA and RNA) that enables the production of proteins in both healthy and cancer cells. As our knowledge of cell biology increased, key structures that benefit cancer cells and that could not be affected by chemotherapy drugs were discovered.

Advances in pharmacology have made it possible to produce molecules that inhibit these key structures in cancer cells. Drugs formulated against a specific group of proteins or structures are called targeted or smart drugs. Many of these proteins and structures are also found in normal cells. Smart drugs deactivate a specific structure in cancer cells that is more active and uncontrollable than in normal cells.

Two main types of targeted therapies are used. The first type consists of intravenously administered, "large molecule" drugs that target receptors on cell surfaces or molecules that attach to these receptors. These drugs cannot enter cells and are produced using biological methods. Because they are digested, they cannot be taken orally and are usually administered intravenously or subcutaneously. Drugs that utilize the receptors themselves to create antibody-like structures have also been developed. These drugs sometimes neutralize cancer cells, sometimes shrink the blood vessels that supply cancer cells, and sometimes stimulate the body's immune cells to fight cancer cells.

The second type of targeted therapies are orally administered, intracellular drugs produced through chemical methods, belonging to the "small molecule" class. These drugs prevent the proliferation of cancer cells or the blood vessels that nourish cancer cells by attaching to certain protein regions that are numerous or overactive and cannot be stopped.

In fact, tamoxifen, which was approved for use in breast cancer treatment in 1977 and exerts a curative effect by blocking the effects of the estrogen hormone in cancer cells, is also a targeted drug and is different from the two groups of drugs described above.

The first large-molecule cancer drug known today as a targeted therapy drug is trastuzumab, which came into use in 1998 and has been effective in advanced-stage breast cancers with increased numbers of receptors called HER-2 on the cell surface.

Imatinib, the first small molecule drug to act by blocking the transmission of growth and malignant differentiation signals from the cell surface to the cell nucleus in cancer cells, found its application in the treatment of chronic myeloid leukemia (CML) in 2001.

A structure called VEGF, released from both normal and cancerous cells, binds to receptors (VEGF-R) in nearby blood vessels, enabling them to extend new branches. The drug bevacizumab, introduced in 2004, prevents new blood vessel formation by capturing circulating VEGFs in the blood and blocking their access to blood vessels. Its effect is exerted not on tumor cells, but on the body's own blood vessel cells. Because it also has an inhibitory effect on other areas of the body involved in blood vessel formation, it is also used in the treatment of diabetic retinopathy, a disease caused by excessive blood vessels in the retina of diabetic patients.

Malignant melanoma (MM), a type of skin tumor, has for many years been one of the most difficult cancers to treat. It is often resistant to older types of drugs, such as interferon, which boost the immune system. MM cells target key areas that the immune system naturally creates to suppress them, activating receptors called CTLA-4 on immune cells and thus deactivating the defense cells. The drug ipilimumab prevents these cancer-fighting cells from being deactivated by covering the CTLA-4 receptors on the surface of immune cells without activating them. Ipilimumab, by correcting the immune system in this way, has proven effective in patients with advanced-stage MM and received approval for use in 2011. In another system where the immune system uses itself more ruthlessly to restrain itself, there are receptors called PD-1 on the surface of immune cells that cause them to die. Cells of some cancers, such as lung cancer, kidney cancer, and MM, affect PD-1 receptors with structures called PD-L1, killing immune cells called T lymphocytes that approach them. You can think of cancer cells as having needles on their surface, and when approaching, attacking immune cells touch them, they burst like balloons.

Nivolumab, a drug that works much like duct tape on a balloon to prevent it from being punctured, prevents the death of immune cells called T lymphocytes by shutting down their PD-1 receptors. It received approval for use in 2014. Later that same year, pembrolizumab, a drug produced by another company and working similarly, also received approval.

The drug atezolizumab works by shutting down PD-L1 structures on the surface of cancer cells—think of it like a needle that bursts a balloon—and received approval for use in 2014. To use drugs that act via PD-L1, the PD-L1 staining intensity (PBY) on cancer cells must be above a certain level.

For reasons that are not yet fully understood, in a small group of patients, these large-molecule drugs that boost the immune system can have the opposite effect of what is expected, meaning they can cause cancer to spread rapidly.

To answer the question of when and for which types of cancer targeted therapies are used, the following four conditions must be met.:

1. For drugs that target cancer cells, there must be a genetic defect in the cancer cells of the patient that can be targeted. To use smart drugs on cancer cells, there must be a driving genetic change, and this must be demonstrated through testing. The chance of detecting this change in patients varies depending on the type of cancer.

   In adenocarcinoma, a type of lung cancer originating from glandular cells, approximately 15% of patients, provided they are non-smokers, have been found to have a genetic change, a driving mutation, in a part of a receptor called EGFR that extends into the cell, and small molecule drugs can be used in treatment.

   In patients with lung cancer that does not have a driving mutation and is not of the small cell type, large molecule drugs may be effective depending on the intensity of PBY.

   Nivolumab can be used in patients with MM, clear cell renal cancer, Hodgkin lymphoma, and epidermoid cell head and neck cancer without the need for any genetic defect, and also in those with some genetic repair genes that are defective. It can also be used in patients with colon cancer.

   In 20% of breast cancer patients, a defect in a gene called c-erb-B2 causes the production of an excessive number of c-erb-B2 receptors extending from the cell surface to the outside of the cell, leading to rapid proliferation of breast cancer cells.

   In all patients with advanced-stage MM, antibody-type drugs such as ipilimumab, nivolumab, or pembrolizumab can be effective, and if there is damage to the BRAF V600 gene, small molecule drugs such as vemurafenib, dabrafenib, trametinib, and cobimetinib can also be effective. For the use of bevacizumab and aflibercept, which prevent vascular formation in patients with advanced-stage colon cancer, no genetic changes are required in cancer cells.

   As the percentages show, not every cancer patient may be suitable for targeted therapy. Research is being conducted on this subject, and new targets and drugs are being found.

2. The development of a targeted (smart) drug that is effective against the genetic disorder. The small molecule drug imatinib binds to the bcr-abl protein, which is found inside the cell and is overactive, thus preventing its activity and curing CML. Imatinib, the first orally administered small molecule smart drug, received approval for use in 2001.

   Among the small molecule drugs used in patients with lung adenocarcinoma with EGFR mutations, gefitinib received FDA approval in 2002 and erlotinib in 2004.

   The large molecule drug trastuzumab binds to and deactivates the c-erb-B2 receptors that extend outside the cell and are overproduced, preventing cancer cells from multiplying. Research on trastuzumab, the first intravenously administered smart drug, began in 1992 on breast cancer patients and it received approval for use in 1998.

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3. The goal of the improved targeted therapy is for the drug to be at least as effective as, or preferably better than, known treatments at the stage of the patient's cancer when it is diagnosed. Some drugs are used as the first option immediately after diagnosis. Others are initially approved for use in advanced stages of cancer that has spread to other organs, and their effectiveness is later proven through research, allowing them to be used in patients with early-stage cancer. In some diseases, conventional chemotherapy drugs may be given before targeted therapy, while in others, they may be given simultaneously.
4. The patient must be able to tolerate the known side effects that may arise from the targeted therapy, or the side effects that occur during use must be managed with minimal harm to the patient. As with all drugs, before targeted therapies are approved for use, research is conducted on hundreds, sometimes thousands of patients, their effects are compared with known treatments, and any side effects are identified.