Fighting Smarter Against Cancer

By: Jimmy Thai

In 1912, Scientific American stated, “The beginning of the end of the cancer problem is in sight.” This bold claim was based on the work of Nobel laureate Paul Ehrlich, who reasoned in the early 1900s that the synthesis of compounds toxic only to diseased cells would yield the creation of new pharmaceutical drugs. Ehrlich applied this principle in the creation of Salvarsan, a compound selectively harmful to the bacterium that causes syphilis. He then tried treating cancer through selective toxicity, but declared in 1915 that he had “wasted 15 years of [his] life in experimental cancer” (1). More than a century later, however, Ehrlich’s dream of selectively targeting cancer cells may finally be realized due to recent developments in targeted chemotherapy treatments.

Generally speaking, cancer is a broad class of diseases marked by the uncontrollable proliferation of dysfunctional cells. According to the Center for Disease Control (CDC), cancer is the second most prevalent cause of death in the United States (2). In 2016, an estimated 1.7 million people will be diagnosed with some form of the disease and about 700,000 people will die from it in the U.S. alone (3). Cancer is a major threat to human health, and continued research into effective treatments is important to society. Among the recent developments in the field of targeted chemotherapy are the refinement of the role of tamoxifen and the creation of a new class of drugs called antibody drug conjugates (ADCs). Both of these advances must be evaluated in the context of the Human Genome Project and personalized medicine.

THE HUMAN GENOME PROJECT AND THE OUTGROWTH OF PERSONALIZED MEDICINE

In 2001, the current director of the National Institutes of Health (NIH) Francis S. Collins asserted that “cancer treatment will precisely target the molecular fingerprints of particular tumors” by the year 2020 (4). Such a claim raises a variety of questions. What did Dr. Collins mean with this statement? What enabled Dr. Collins to make such a bold claim? How well is Dr. Collins’ claim holding up against the test of time?

The answers to the first two questions reside in Dr. Collins’ monumental role in the most groundbreaking biological project of the 21st century. Before he became the director of the NIH, Dr. Collins was the director of the Human Genome Project (HGP). His bold prediction about cancer was based on the HGP’s remarkable findings. The completion of the HGP in April 2003 meant that the DNA sequence of the human species had been decoded and recorded. From this information, scientists were able to conclude that most diseases, including cancer, contain a hereditary component. Because diseases can ultimately be traced back to sequences of DNA called genes, the findings of the HGP allowed for the development and refinement of gene-specific designer drugs to fight illness. The majority of these drugs work by targeting the protein products coded for by a gene. This concept forms the basis of personalized medicine, in which patients are assigned different therapeutic regimens based on their genetic profile (5).

One major example of the application of personalized medicine to cancer treatment is the field of targeted chemotherapy treatments, many of which work by interfering with cell division and/or DNA replication. Standard chemotherapy treatments affect both healthy and cancerous tissue indiscriminately. In contrast, targeted therapies are specifically designed to kill cancerous cells, hence minimizing the collateral damage done to the rest of the body. This precision in drug targeting is likely what Dr. Collins envisioned with his 2001 remarks.

TEACHING AN OLD DRUG NEW TRICKS: TAMOXIFEN

In the typical course of cancer treatment, tumors are surgically removed and then the patient is given adjuvant therapy drugs to prevent the tumor from coming back. As such, both finding new and refining current adjuvant therapies represent major areas of chemotherapy research.

The first successful targeted cancer chemotherapy was tamoxifen, which was approved for patient use by the Food and Drug Administration (FDA) in 1977. Tamoxifen is mainly used as an adjuvant therapy drug for breast cancer, and it belongs to a class of medications known as selective estrogen receptor modulators (SERMs), compounds that have either agonistic (promotive) or antagonistic (inhibitory) effects on estrogen receptors. In a certain subset of breast cancers that are estrogen receptor positive, estrogen fuels tumor growth, and tamoxifen works by inhibiting estrogen receptor activity (6).

Although estrogen seems to play a harmful role in breast cancer, recent scientific data suggest that the truth is much more nuanced and complex. Recent experiments within the past decade support the idea that after breast cancer cells are treated long-term with tamoxifen, the return of estrogen may actually induce apoptosis (cell death) (7). Thus, estrogen can paradoxically both stimulate and inhibit the growth of breast cancer cells under different circumstances. In the words of Dr. Virgil Craig Jordan, a leading researcher in the field, “the dramatic cell kill I get with estrogen is better than anything I saw with tamoxifen” (8). The phenomenon of estrogen-induced apoptosis is a relatively new idea important for two reasons. First, this discovery suggests that the most effective therapy option may not be a single treatment but rather a combination of different treatments, such as tamoxifen followed by estrogen. Second, it illustrates that even well established targeted chemotherapies may be made more effective in light of current scientific data. For women with tamoxifen-resistant tumors, the combination of tamoxifen followed by estrogen offers real therapeutic promise. Recent tamoxifen research may lead to the development of better treatments for estrogen receptor positive breast cancers.

MERGING IMMUNOTHERAPY WITH CHEMOTHERAPY: ANTIBODY-DRUG CONJUGATES

Returning to the story of Paul Ehrlich in the early 1900s, Ehrlich failed to create targeted cancer drugs because he failed to account for the fact that proteins expressed by cancerous cells, unlike those of foreign bacteria, are innate to one’s body. Thus, it is much more difficult to find a drug that is specific to tumors. In addition, Ehrlich and his contemporaries had no way of intentionally synthesizing compounds to limit biological activity. They had to rely on luck. Nearly a century later, the constraints that limited Ehrlich are no more. The lifting of these limitations has led to the development of new chemotherapeutic drugs, including antibody-drug conjugates (ADCs).

ADCs are created by linking chemotherapeutic agents with proteins called antibodies. All antibodies have a specific shape and thus only bind to and interfere with specific cell receptors. Because certain types of cancer overexpress certain receptors, the isolation of antibodies specific to these receptors provides a promising way of singling out cancerous cells for the internalization of toxic drugs. Given the enormous potential of ADCs, it is important to make clear their benefits and limitations.

A major limitation of ADCs is that they are only effective in the subset of cancers that overexpress protein receptors relative to normal cells. For cancerous cells, the receptors must be expressed at least twofold more than in normal cells. Even if this main criterion is met, a number of other constraints limit the potential of ADCs. For instance, ideal cell surface receptors are quickly recycled back into the cell after an ADC binds. This allows for quicker internalization of the chemotherapeutic agent. In addition, there is an absolute minimum level of receptor protein expression required, as sufficient amounts of the toxic chemical must be internalized for the ADC to be effective (9).

Despite these limitations, ADCs are still truly revolutionary in the field of targeted chemotherapy. Unlike other such drugs, which were identified on accident or through brute force trial and error experiments, ADCs can be engineered to specifically bind to particular cell surface proteins. This process of antibody engineering is made possible by monoclonal antibodies (mAbs). Scientists can now make massive quantities of any specific antibody.

Two of the most important ADCs include brentuximab vedotin and ado-trastuzumab emtansine, which were approved by the FDA in 2011 and 2013 respectively. Brentuximab vedotin consists of the monoclonal antibody brentuximab and the chemotherapeutic agent monomethyl auristatin E (MAME). Because brentuximab is specific to the CD30 protein, cancers that overexpress the CD30 protein such as classical Hodgkin’s lymphoma (cHL) and anaplastic large-cell lymphoma (ALCL) can be targeted specifically with the ADC (10). Likewise, ado-trastuzumab emtansine consists of the monoclonal antibody trastuzumab and the chemotherapeutic agent DM1. Because ado-trastuzumab emtansine targets the HER2 receptor, which is overexpressed in cases of HER2-positive breast cancer, HER2-positive cells can be specifically targeted (11). The development of ADCs is a relatively new advancement in the field of targeted chemotherapy, but it provides much promise for particular types of cancer.

CONCLUSION

We are now four years away from the target date set forth by Dr. Collins’ bold prediction about cancer treatment. So how well has Dr. Collins’ assertion held up over time? Within the span of a decade and a half, the field of targeted chemotherapy treatment has evolved rapidly, specifically through the refinement of tamoxifen therapy and the development of antibody-drug conjugates. Both of these advances give credence to Dr. Collins’ claims. As evidenced by recent progress in the field of targeted chemotherapies, society is getting warmer in the fight against cancer.

Jimmy Thai ’20 is a freshman in Matthews Hall.

WORKS CITED

[1] Jordan, V. C. Cancer Research, 2001. 61(15), 5683-5687.

[2] Centers for Disease Control and Prevention. http://www.cdc.gov/nchs/ fastats/leading-causes-of-death.htm (accessed Sep.25 2016).

[3] National Cancer Institute. https:// http://www.cancer.gov/about-cancer/understanding/statistics (accessed Sep. 25 2016).

[4] Testimony of Francis S. Collins. http://www.hhs.gov/asl/testify/t010725b. html (accessed Sep. 25 2016).

[5] Collins, F. S.; McKusick, V. A. Journal of the American Medical Association. 2001, 285(5), 540-544.

[6] Jordan, V. C. European Journal of Cancer. 2008, 44, 30-38.

[7] Lewis-Wambi, J. S.; Jordan, V. C. Breast Cancer Research [Online], 11. https://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr2255 (accessed Sep. 26 2016).

[8] Gupta, S. Proceedings of the National Academy of Sciences of the United States of America. 2011, 108(47), 18876- 18878.

[9] Srinivasarao, M. et al. Nature Reviews: Drug Discovery. 2015, 14, 203-219.

[10] Perini, G. F.; Pro, B. Biologics in Therapy [Online]. 2013, 3(1), 15-23. https:// www-ncbi-nlm-nih-gov.ezp-prod1.hul. harvard.edu/pmc/articles/PMC3873074/# (accessed Sep. 30 2016).

[11] Haddley, K. Drugs of Today [Online]. 2013, 49(11), 701-715. https://journals-prous-com.ezp-prod1.hul.harvard. edu/journals/servlet/xmlxsl/dot/20134911/ pdf/dt490701.pdf?p_JournalId=4&p_refId=2020937&p_IsPs=N (accessed Sep. 30 2016).