Molecular targets of cancer as basis for new drugs and immunotherapy

(Second of two parts)

What Hanahan and Weinberg did was to provide a unifying, simplified concept that would make all cancers understandable in terms of a few underlying principles. They predicted that cancer research would develop into a logical science, where the complexities of the disease, described both in the laboratory and the clinic, could be reduced to a few acquired molecular, biochemical and cellular traits.

While the complexity in cancer is daunting, a general strategy for treatment and cure became evident from the new molecular findings which revealed some common major targets. And so while personalized diagnostics and treatment may be the goal of the future (there must be ways to bring down the prohibitive costs), presently molecular target drugs in combination with other forms of therapy are being used to treat both solid tumors and circulating cancers with some success. Combination drug therapy has actually been used in cancer for many years, e.g., methotrexate and 5-fluorouracil, or CAT (Cyclophosphamide, Adriamycin, Taxol). (This strategy has been most dramatic and successful for HIV/AIDS which is held at bay if a patient is given a cocktail of drugs that inhibit key enzymes in viral replication and infection, i.e., reverse transcriptase, integrase, protease.) The idea is that targeting two or more pathways or attacking cancer on several fronts, at the same time, would provide a better chance for a “100 percent kill.”

Today the fastest growing field in cancer therapy is the use of biologicals, principally therapeutic antibodies. Several antibodies have been developed that target and inhibit the family of proteins known as epidermal growth factor receptors (EGFRs) found on the cell surface. EGFRs are mutated in many cancers, and as a consequence the receptor keeps sending growth signals to the nucleus of the cell, which then results in unabated cell cycling and cell division. These EGFRs are actually EGFR-RTKs; RTKs are receptor tyrosine kinases, meaning they are also enzymes, and therefore “druggable” targets. [RTKs are transmembrane proteins, which means part of the protein is found on the cell surface (the receptor component), a part transverses the cell membrane (transmembrane), and part is found on the intracellular surface of the membrane (the enzyme component).]

The EGFR-RTK therapeutic antibodies, e.g., Herceptin, exert their effect by binding the receptor component on the cell surface (antibodies are large and won’t enter the cell). Also used are small molecule drugs, e.g., Iressa, Tarceva, that can enter the cell to inhibit the tyrosine kinase component of the EGFR-RTKs found inside the cell. So here we have an example of combination therapy, involving an antibody and a drug, inhibiting an important upstream protein in a growth signaling pathway in cancer. Then there is the widely used therapeutic antibody Avastin which inhibits angiogenesis or capillaries forming around tumors. The antibody binds the vascular endothelial growth factor (VEGF) which prevents VEGF from binding its receptor (VEGFR) that would trigger vascular growth. Anti-growth signaling and anti-angiogenic therapies are combined to provide a more effective treatment of cancer.

Therapeutic antibodies are an example of passive immunotherapy (passive meaning your body does not have to produce the antibody response by itself). Is there active immunotherapy or something close to vaccination or immunization in cancer treatment? Yes, and this may be what comes closest to personalized therapy in cancer.

It is almost ironic that cancer immunotherapy is now a fast growing field, since cancer can be viewed as a failure of the immune system or of immune surveillance. Our immune system is not able to (or not trained to) detect fine differences between normal and cancer cells in the initiation phase or early stages of cancer. Cancer cells are not viewed as foreign, or “non-self,” and therefore the immune system does not get rid of them.

Active immunotherapy employs ways to prime and train our immune system to detect cancer cells and get rid of them better. In one form, certain tumor antigens or markers, which have been found present in the patient’s cancer, are used as an immunogen and presented properly by antigen presenting cells (APCs), e.g., dendritic cells (DCs), to cytotoxic T cells. The T cells (and B cells) are trained (they develop a specificity) to detect these same antigens in cancer cells in the body. In another form, the patient’s tumor tissue itself is processed to serve as the immunogen. What better source of tumor markers would a person have than his own tumor? This would come closest to personalized immunotherapy.

The challenges in treating solid tumors such as breast, lung and colorectal cancer are still great. Penetrability of solid tumors poses a major problem in all forms of immunotherapy. For circulating, blood tumors such as AML, not only is this not a problem, there is great advantage of being able to remove and return components of the blood, including the blood cells… and there is a possibility for successful transplants from well-matched donors. The real challenge with AML (ACUTE myeloid leukemia) though is that blast cells are fast growing and dividing, and rapidly mutating.

My friend who had AML ultimately received different types of active immunotherapy. Initially, an “autologous” transplant was tried, but it failed. Autologous means that the transplant was from her own blood stem cells, which had been cleared of blast cells and rated “zero blast” after rounds of chemotherapy. When she had a recurrence, these cells were cultured and introduced to her. However, after some time, the AML recurred because the “zero blast” was not really zero. Also, IL-2 (interleukin-2 is a cytokine which stimulates cytotoxic T cells to proliferate and kill cancer cells) therapy had been tried but the response mounted by IL-2 was not sufficient to fight the blast cells.

The final attempt was an “allogeneic” transplant, meaning stem cells came from another individual. Sadly, she had no relatives with a good match. But there is an international blood registry that allows the matching of unrelated donors (MUDs). Out there are healthy blood donors who are willing to help patients with leukemias and other blood disorders. All that was needed was a good match of cell surface markers known as HLA- A, B and C (human leukocyte antigens) between the host and donor to avert a strong immune rejection known as GVDH (graft-versus-host-disease). After five years of waiting, a donor with a match of nine out of 10 HLAs was found. Her rally to survive had paid off. 

In preparation for the allogeneic stem cell transplant, my friend had to undergo a final wipeout of her blast cells — another chemotherapy, followed by radiation therapy, after which healthy normal stem cells from the donor were introduced to her by a simple blood transfusion. The donor’s healthy cells replaced her blast cells and continue to suppress whatever abnormal cells may arise in what is thought to be the beneficial effects of a mild GVHD. She needs life-long immunosuppresants, much like a kidney transplantee, but by all other measures, she lives a normal, healthy life. 

At the leading leukemia center known as “The Hutch” (Fred Hutchinson Center) in Seattle, for AML, a new antibody-radioisotope conjugate of anti-CD45 and Iodine-131 is being used in myoablative therapy before transplant, and stem cell transplant from umbilical cord blood is used for those who cannot find well-matched donors. Clearly, there are major advances in cancer treatment, and with many more molecular markers and targets being elucidated, more therapeutic breakthroughs and options will become available in the next few years. The prediction is the rise of effective combination and personalized therapies that address the complex and unique features of an individual’s cancer.

We continue to learn many lessons from personal experiences that are related to our academic work. One is to appreciate what some of our young well-trained researchers are doing in cancer research in the country today. Dr. Francisco Chung works at the Lung Center of the Philippines and has a few success stories of immunotherapy in solid tumors (with molecular evidence). Dr. Jose Enrico Lazaro now leads the Antibody and Molecular Oncology Research (AMOR) Program Part 2 funded by the DOST to continue the development of immunoliposomal drug therapy which we started with Drs. Eduardo Padlan and Ameurfina Dumlao-Santos several years ago. Another is to keep pursuing basic research. We continue to search for anticancer drugs from marine organisms, with pro-apoptotic effects, and we work on animal immunotherapy models for cancer in my laboratory. We may not be able to reap direct benefits to ourselves, our family or friends presently, but perhaps basic cancer research will help in the treatment and cure of other Filipinos in the near or distant future.

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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. She is a member of the National Academy of Science and Technology. E-mail her at [email protected].