10 CHAPTER 1 GENERAL INTRODUCTION Accounting for almost one in six deaths, cancer is the second leading cause of death worldwide1. In 2020, an estimated 19.3 million new cancer cases occurred, and nearly 10 million people have died from the disease2. The global cancer burden continues to increase and a 47% rise in incidence is expected between 2020 and 2040 to an incidence of 28.4 million cases2. A GENETIC DISEASE Cancer is a generic term for a large group of diseases characterized by the uncontrolled growth and spread of abnormal cells that can result in death if not treated1. It is a genetic disease with nine essential characteristics (Hallmarks): self-sufficiency in growth signals, evasion of growth suppressors, resistance to cell death, replicative immortality, induction of angiogenesis, activation of invasion and metastasis, reprogramming of energy metabolism, evading immune destruction and the creation of a “tumor microenvironment”. Underlying these Hallmarks are two enabling capabilities: genome instability and mutation and tumor-promoting inflammation3,4. Using these Hallmarks to describe the pathophysiology of cancer provides a better understanding of the drivers and enablers of the disease, and, equally important, may contribute to the development of new effective systemic anti-cancer treatments. SYSTEMIC ANTI-CANCER TREATMENT: CHEMOTHERAPY The first written prescriptions of remedies for the treatment of cancer date back to 2000 BC, usually in the form of ointments, medicated herbal solutions and powders5. Luckily, we have come a long way since then, and the systemic anti-cancer therapies have become more and more effective. Between 1948 and 1956, folic acid antagonists, vinca alkaloids and methotrexate were introduced as effective chemotherapies for the treatment of different types of cancer5. These agents were among the first modern chemotherapeutic drugs and are still in use today. Since the late 1950’s, systemic anti-cancer therapies have continued to improve in terms of efficacy and survival due to the discovery of new chemotherapeutic agents, new combinations of drugs, new dosing regimens and the use of chemotherapy (neo)adjuvant to surgery and radiotherapy6. Conventional chemotherapy interferes with the DNA, hindering cell division and thereby stopping tumor growth but also damaging healthy tissues. Not all tumors respond (equally) to treatment with chemotherapy while most patients experience (serious) toxic side effects. It has proven to be difficult to upfront predict which patients will benefit from the treatment. Part of the solution to the problem of treatment selection for individual patients may lie in the fact that cancer is a genetic disease, which is characterized by dysregulation of growth signaling cascades and the escape from suppressive signaling and the immune response. NEW CLASSES OF ANTI-CANCER DRUGS In the past 30 years, global overall cancer survival and five-year relative survival has improved significantly7. Many factors have contributed to this worldwide decrease in mortality7. Development of, and access to, new types of anti-cancer drugs has played a major role in multiple tumor types. Especially drugs that interfere with aberrantly activated signaling cascades (i.e.
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