(First of two parts)
A few months ago, in this column I wrote about a close friend who has survived AML (acute myeloid leukemia) for more than 10 years. It was in an article on “Anticancer drugs from land and sea.” I recounted how the synthetic drug cytarabine (Ara-C), used to treat AML, was modeled after spongothymidine (Ara-T) and spongouridine (Ara-U), the first anticancer compounds isolated from marine sponges in the mid-1950s. This discovery gave birth to the research field known as marine natural products (MNPs). Because I was involved in MNP research, I was asked by my friend and her family to help out during the early days of her disease.
AML is a fast-growing cancer of bone marrow and blood cells. In AML, abnormal blast cells proliferate and do not develop into white blood cells which the body requires to fight infection. Abnormal red blood cells and platelets crowd out normal cells which the body needs to prevent bleeding. Infections and bleeding are manifestations of AML. Cytarabine acts as an antimetabolite which inhibits DNA synthesis, causing blast cells, as well as fast growing normal cells such as immune cells, to die. Because immune cells are wiped out, a cancer patient in chemotherapy is extremely vulnerable to all kinds of infections. (Of course, if an AML patient received no treatment, infection would also set in.) And because cancer cells possess genetic instability, some AML cells are able to “survive” the drug and become drug-resistant, i.e., genes are mutated to produce a protein that pumps the drug out of the cell, and to become a more aggressive form of blast cells.
All that happened to my friend. After a few cycles of chemotherapy followed by a few months of remission, the AML recurred, not once, but a few times. However, she was young and she had a strong fighting spirit. We told her that every additional year of survival would offer new possibilities for a cure. So she struggled and survived till the time she could receive state-of-the-art immunotherapy and stem cell transplant (SCT) therapy, in the best hospitals in Canada and the USA.
For decades, anticancer drugs had been targeted to only the S (synthetic) and M (mitotic) phases of the cell cycle. (Many examples of these drugs, aside from cytarabine, were mentioned in the previous article.) In 2000, in a landmark review paper titled “The Hallmarks of Cancer” [Cell (2000) 100 (1): 57-70], D. Hanahan and R.A. Weinberg presented what they thought were six “acquired capabilities” in cancer. All cancers shared genetic alterations in several pathways in the cell that led to: 1) self-sufficiency in growth signals (in the absence of growth factors and hormones, cells continue to grow); 2) insensitivity to anti-growth signaling (even when nutrients outside the cell are low, the cells continue to grow); 3) evasion of apoptosis or programmed cell death (cells do not die even if their DNA or proteins are damaged); 4) sustained angiogenesis (cells stimulate capillaries to grow around them to acquire nutrients); 5) limitless replicative potential (the ends of chromosomes called telomeres do not shorten, or are maintained, allowing cells to grow and divide many more times than normal); and 6) tissue invasion and metastasis (cells become motile and invade other organs and tissues).
The authors likened the cell to an integrated electrical circuit. Signaling pathways are regulated by key proteins which behave like conductors, transducers, amplifiers, adaptors or rheostats, and feedback loops and cross-talk links among the six pathways make operations in the cell very sensitive to signals and highly synchronized. In cancers, many of the key regulatory proteins are mutated, and so the cell quickly acquires the new capabilities enumerated above and the cells’ behavior goes awry. Since 2000, the list of mutated genes and proteins found in various cancers has continued to grow. These new findings opened up research on new “druggable” targets in cancer, e.g., enzymes called kinases that can be effectively inhibited by small molecule drugs. Very significantly, it also ushered in the era of new immunotherapy regimens in cancer.
Further, the gene and protein mutation profile in the cancer of one organ or tissue proved to be different from that in another organ or tissue. More correctly, cancer is referred to as a group of diseases of about 100 types, each with many subtypes. Ultimately, each person’s cancer proves to have its own unique profile. And so what does this tell us about cancer? That it is a very complex disease and very challenging to fight, especially if detected at an advanced stage, or if it is one with fast-growing and rapidly dividing cells like AML. How could only one or two drugs serve as a common cure for everyone’s cancer, if each has its own suite of altered pathways and proteins that need to be inhibited? Logically or ideally, it would seem like the treatment of one’s cancer should be individualized — or personalized. (To be continued)
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Gisela P. Padilla Concepcion, Ph.D., is a professor in the Marine Science Institute, UP Diliman, where she teaches graduate courses and leads research in marine drug discovery and related biomedical research. She also has projects on vaccine candidates for infectious diseases and animal immunotherapy models for cancer. She is a member of the National Academy of Science and Technology. E-mail her at gpconcepcion@gmail.com.