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Combination Therapies and Personalized Medicine

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Combination therapy combines two or more treatment regimes or cancer drugs to target cancer-related metabolic pathways in the cell.

Conventional therapies are more likely to fail because a single drug can only target one cancer-related pathway at a time. This often leads to the emergence of drug-resistant cancer cells during the course of treatment. On the contrary, combination therapy simultaneously targets different pathways and different cellular enzymes, thus reducing the chances of drug resistance.

The combination of different drugs also helps to lower their therapeutic dosage as well as increase the treatment efficiency due to a synergistic effect.

It also increases the cytotoxicity specifically in cancer cells while simultaneously reducing drug side effects on the normal cells. For example, caspase inhibitors can enter a normal cell and a cancer cell alike and inhibit apoptosis.

Similarly, the cytotoxic drug flavopiridol can induce apoptosis in both normal and cancer cells.

When both drugs are used together during therapy, the normal cells as well as cancer cells uptake both - caspase inhibitors and flavopiridol. In normal cells, both drugs cancel each other's effect, and the cell survives.

However, in the cancer cells, the overexpression of the ABC transporter selectively pumps the caspase inhibitor out of the cell, leaving behind the flavopiridol that induces apoptosis.

Cancer is a complex disease involving multiple genetic mutations and phenotypes that vary amongst patients as well as in different stages of the disease. Therefore, a patient-specific treatment may be more beneficial than one fit for all treatment.

Personalized cancer treatment is a precise approach that relies on the patients' genetic profile to guide the right therapy for more efficient cancer prevention and treatment.

For example, 15-20 percent of all leukemia cases are caused by a chromosomal translocation between chromosomes 22 and 9. It creates a fusion kinase protein BCR-ABL1 that triggers rapid cell proliferation.

Imatinib is a specific kinase inhibitor that inhibits the activity of BCR-ABL1 protein and slows down the growth of mutant cells. Genetic screening of leukemia patients for this particular mutation helps decide the use of imatinib in such patients and increases the survival rate.

Overview

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Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.

The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and acidic microenvironment. In order to overcome this, cancer cells overexpress the enzyme carbonic anhydrase that catalyzes the reversible conversion of carbon dioxide to bicarbonate and neutralizes the acidic tumor microenvironment.

Acetazolamide is a carbonic anhydrase inhibitor that inhibits the enzyme carbonic anhydrase accelerating the death of cancer cells. Another drug, sulforaphane, activates certain anti-cancer responses and suppresses tumor progression. Combined administration of acetazolamide and sulforaphane results in the enhanced killing of cancer cells and reduced tumor progression.

Personalized medicine or precision medicine

Precision medicine or personalized medicine is an advanced technique that allows treatments based on the genetic background of the disease. The treatment is designed based on specific abnormal genes or proteins in the tumor cells of each individual. The details about cancer genetics are usually obtained from a tumor biopsy. The morphology of the tumor cells followed by genome sequencing reveals mutations or changes in the specific biochemical pathways. Based on this information, drugs and treatment regimens are decided.

Personalized medicine has four significant attributes. First, it is personalized. It integrates the genetic profile of patients to strengthen and target the therapy and reduce drug toxicity. Second, it is preventive. Females with mutations in BRCA1 or BRCA2 genes have a higher disposition of developing breast cancer. Such genetic data allow disease management through early intervention. The third attribute is predictive. Gene expression profiles are used to assess the risk of metastasis in patients with early-stage cancer. Based on the expression profiles, doctors can decide whether to use hormone therapy or more aggressive chemotherapy. Fourth is participation. The personalized treatments are less toxic and more effective. Hence, patients are more likely to comply with their treatments.

Transcript

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Combination therapy combines two or more treatment regimes or cancer drugs to target cancer-related metabolic pathways in the cell.

Conventional therapies are more likely to fail because a single drug can only target one cancer-related pathway at a time. This often leads to the emergence of drug-resistant cancer cells during the course of treatment. On the contrary, combination therapy simultaneously targets different pathways and different cellular enzymes, thus reducing the chances of drug resistance.

The combination of different drugs also helps to lower their therapeutic dosage as well as increase the treatment efficiency due to a synergistic effect.

It also increases the cytotoxicity specifically in cancer cells while simultaneously reducing drug side effects on the normal cells. For example, caspase inhibitors can enter a normal cell and a cancer cell alike and inhibit apoptosis.

Similarly, the cytotoxic drug flavopiridol can induce apoptosis in both normal and cancer cells.

When both drugs are used together during therapy, the normal cells as well as cancer cells uptake both - caspase inhibitors and flavopiridol. In normal cells, both drugs cancel each other's effect, and the cell survives.

However, in the cancer cells, the overexpression of the ABC transporter selectively pumps the caspase inhibitor out of the cell, leaving behind the flavopiridol that induces apoptosis.

Cancer is a complex disease involving multiple genetic mutations and phenotypes that vary amongst patients as well as in different stages of the disease. Therefore, a patient-specific treatment may be more beneficial than one fit for all treatment.

Personalized cancer treatment is a precise approach that relies on the patients' genetic profile to guide the right therapy for more efficient cancer prevention and treatment.

For example, 15-20 percent of all leukemia cases are caused by a chromosomal translocation between chromosomes 22 and 9. It creates a fusion kinase protein BCR-ABL1 that triggers rapid cell proliferation.

Imatinib is a specific kinase inhibitor that inhibits the activity of BCR-ABL1 protein and slows down the growth of mutant cells. Genetic screening of leukemia patients for this particular mutation helps decide the use of imatinib in such patients and increases the survival rate.

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