Cancer

Under the Microscope: Malignancies of Cancer Research and Why Onco-Therapeutic Development is Failing Us | by Samuel Samous | Oct, 2021

Samuel Samous

Thousands of cancer researchers worldwide pipette media solutions, culture cells, and conduct experiments in the hopes of someday discovering that one unique “wonder drug,” a viable cancer treatment. As cancer tears families apart and separates loved ones in an undignifying fashion, cancer researchers desperately search for results to arguably one of the most atrocious pathologies in the present age. The gravity of our current situation is bleak, as the National Institute of Health National Cancer Institute asserts that “in 2018, there were 9.5 million cancer-related deaths worldwide,” a number that seems not to wane with each coming year (“Cancer Statistics”). The average human lifespan is rising, so treating cancer and finding new approaches to onco-therapeutic drug development has become a pressing matter, now more than ever. Unfortunately, when inspecting the grim nature of our prevailing state of affairs, it is clear that cancer research has failed us: billions of dollars spent, many years wasted, and for what? Academic estimates show that 97% of cancer drugs developed today utterly fail before they ever make it to market, yielding no results in terms of appropriate treatments and risking the lives of countless humans and other animals (Belluz). When coupling so many cancer drug development failures with the fact that oncological research is an exceedingly expensive venture, costing about $2.6 billion over 10 years, we have to question whether so much money and resources are either poorly allocated or wasted completely. Dr. Nipha Chaicharoenaudomrung claims that the field of cancer research shows the worst promise of drug development and treatment compared to other disease treatment studies, citing an unprecedented 95% drug response failure rate in human test subjects post in vitro testing (1067). Working as a cancer researcher in the Center for Molecular Medicine at Stony Brook University, I began to observe notable flaws in current protocol, postulating that procedural flaws may be the cause of poor onco pharmaceutical outcomes. The use of immortalized cell lines, 2-dimensional monolayer tissue culturing techniques, and utilization of reductionist approaches such as targeted therapies are the flaws of modern cancer research, which yield horrific outcomes. Though it may seem counterintuitive to revamp contemporary cancer research protocols, after assessing the general trends and associated techniques related to onco-pharmaceutical development, it is reasonable to state that ineffectiveness, inefficiencies, and ethical quandaries runs rampant in cancer research, and a radical reformation of modern approaches is necessary — specifically, a change in culturing techniques, target therapies, and the use of immortalized cell lines.

The utilization of tissue culture techniques, more precisely the growth of various primary or immortalized cells on a 2-dimensional dish or well plate, lies at the heart of cancer research. Thanks to monolayer tissue culturing assays, scientists unveiled some of the most vital discoveries relating to cancer’s mechanistic and pharmaceutical aspects, so credit should be given where it is due. Despite the relative utility offered by 2-dimensional tissue culturing, the technique has grown somewhat outdated, wasting more resources and doing far more harm than good in the long run. It shouldn’t come as a surprise that humans and other animals aren’t simply petri dishes; we aren’t 2-dimensional creatures, and therefore, do not have physiological mechanisms that mirror monolayered in vitro models. Our bodies are systems of immense complexity and nuance, interacting with a plethora of factors that should, for the most part, be catered to when generating in vitro models for research. To generalize any findings from a 2-dimensional monolayer of cells to our 3-dimensional tissues and organs seems imprudent, and that’s why onco-pharmaceutical development has the observed poor outcomes it does. Many cancer researchers, including myself, have called for a more efficient and effective technique(s) to generate results with actual significance, not just false hope. 3-Dimensional spheroid culturing techniques are a novel and promising method that scientists should add to the guidebooks and protocols of every lab developing cancer drugs, and for labs developing treatments for other pathologies. The reasoning for such a drastic and radical change is that, although spheroid tissue cultures are a slower method for growing cancer cells and performing assays, they are a far better mimicry of in vivo conditions than monolayer tissue culturing. This change would address many of the present issues surrounding 2-Dimensional tissue culturing, providing more realistic drug interactions, structural interactions such as basoapical polarity, proliferation zones, and 3-Dimensional environmental interactions such as cell-cell and cell-extracellular matrix interactions. A study by Japanese scientists showed that multicellular spheroids were less sensitive to well-known cancer drugs than monolayer tissue cultures. This is attributed to 3-D MCSs doing a better job simulating in vivo pathophysiological properties of tumors than 2-dimensional monolayer cultures (Imamura). At the very least, considering 3D MCS culturing before researchers jump to animal models and other preclinical trials seems sensible.

Although changing culturing techniques is a fantastic step in the right direction, it is still a drop in the metaphorical bucket of statistically significant data. When researching metastasis, migration, and invasion of breast cancer, I used an immortalized triple-negative metastatic breast cancer cell line, famously known as the MDA-MB-231 cell line. A 51-year-old caucasian female with a metastatic ductal cell adenocarcinoma was biopsied. Ultimately, her highly aggressive biopsy was cultured and sold by research provisioners, making her cells “immortal.” Although it is considered a versatile and quintessential cell line for metastatic cancer research, not every person with metastatic ductal cell adenocarcinoma shares the same environmental exposures, general genetics, oncogenes, or tumor suppressor gene mutations. Use of immortalized cell lines that were selected for (with bias) and recultured (or “passed) many times over is a careless mistake on the part of all cancer researchers. A key characteristic of cancer is its propensity to acquire mutations with each mitotic cycle because of deregulated proliferative mechanisms. Immortalized cell lines are not accurate in vivo cellular biology models because of their variability and systematic error that increases with each passage. The works of Kaur and Dufour assess many of the significant drawbacks with the use of immortalized cell lines, highlighting that the majority of cell lines in use today are contaminated with HeLa cells (1). These observations can be a potential reason why it is difficult for researchers to generalize their findings to a larger population, and why using immortalized cells is so careless. The cost is no upside either, at a starting price of USD 603.00 on Sigma Aldrich as of October 17, 2021. Many might say that those costs pay for themselves over a course of time since this specific cell line can be passed dozens of times over, amplified to many different plates, and frozen in liquid nitrogen, but scientists can do the same with primary tumor cell biopsies for much less. It also doesn’t cover the costs when factoring in other costs for maintaining and using them. If utilization of immortalized cells generated more relevant results, then the cost would indeed be worth it, but instead, immortalized cells tend to be wasted, producing data that lacks any promise. At Stony Brook University Hospital and its associated clinics, hundreds of cancer patients are seen and biopsied every year, and the same goes for multiple medical institutions around the United States. These biopsy samples are a far better model for cancer treatment within this specific community, accurately depicting the region’s environmental factors. Primary cancer cells are cheaper to acquire than immortalized cells, being free in many cases. Working with such a diverse set of cell types will lead to better results and applicable data sets. Since each cancer has unique epigenetic exposures, oncogenetic mutations, and/or tumor suppressor mutation, it may have to be identified with various assays and sequenced each time a sample is collected to understand that specific cancer’s underlying characteristics. Immortalized cell cultures shouldn’t be done away with altogether, but instead avoided unless necessary to use. Primary tumor cells should be the standard for cancer research to generate more statistically and applicably significant data for clinical trials. To expedite the standardized use of primary cell lines, hospitals, oncological physicians, and researchers should cooperate in formulating a system that allows patients to donate their biopsies for science.

Lastly, We as scientists should address target therapies as well. A targeted therapy is any drug or treatment that binds to and alters a specific nucleic acid sequence or molecule in a signaling pathway. In the case of cancer, tumorigenic, angiogenic, and metastatic pathways have been closely studied to find a specific “bad actor” molecular component to down-regulate or eliminate, and vise versa for restoring or upregulating the missing or poorly functioning “good actors” molecular components. This form of cancer therapy seems ingenious on paper, but reality sings to the tune of a different song. Utilization of this reductionist approach for cancer drug development has been quite ineffective in treatment output for reasons not yet understood, commonly failing in clinical trials. Dr. Ann Lin and her colleagues suggest that the reason why 97% of targeted therapeutics fail is that the majority of cancer drugs that were designed and tested in vitro to interact with a given molecular target killed cells by “interacting with proteins other than its reported target” (2). This leaves many researchers, including myself, disheartened at the lack of results generated when target therapies go to clinical trials. We as cancer researchers need to change our reductionist frame of study to a more global approach, one in which we start from a general observation of an onco-pathological phenomenon and work our way down towards the potential target, rather than focusing on an isolated target within a pathway and working our way up. The reasoning behind this prescribed alteration in approaches is because, as stated above in the works of Dr. Lin and her colleagues, we often don’t hit the targets we intend to, meaning we most likely have the mechanistics wrong. Cancer researchers can learn much more valuable information by starting from the basics, rather than the complex.

The world of cancer research is rife with ineffective protocols and approaches, and switching out 2-dimensional tissue culturing techniques for 3-dimensional spheroid culturing, more use of primary cell line biopsies instead of immortalized cell lines, and incorporating a global approach in our therapies are some of the many great solutions. As cancer researchers, it is our professional and moral duty to those devastated by this illness to adopt better methods of study and development. Although this is a task of considerable difficulty, we should still strive to adapt to inadequate results instead of replicating them. Fortunately, we as a society can all participate in advancing the efforts of groundbreaking cancer research and onco-pharmaceutical development. As everyday tax-paying citizens, we should be more vocal about scientists addressing issues in current research standards. And to those that are donors for cancer research efforts, it is judicious to know where your money goes, as this is essentially voting with a dollar. Wasting countless valuable resources and inflicting harm, even death in some cases, is a complete ethical violation on the part of all those who continue to ignore this issue as bodies pile up. So many people struggle with this pathology today, so many people are pointlessly and tragically lost, and if we as scientists wish to make this pathology a remnant of the past, it only starts by introspecting and changing the present.

Works Cited

“Cancer Statistics.” National Cancer Institute, https://www.cancer.gov/about-cancer/understanding/statistics.

Belluz, Julia. “Most Cancer Drugs Fail in Testing. This Might Be a Big Reason Why.” Vox, 16 Sept. 2019, https://www.vox.com/2019/9/16/20864066/cancer-studies-fail.

Imamura, Yoshinori et al. “Comparison of 2D- and 3D-culture models as drug-testing platforms in breast cancer.” Oncology Reports vol. 33,4 (2015): pp 1837–43. doi:10.3892/or.2015.3767.

Kaur, Gurvinder, and Jannette M Dufour. “Cell lines: Valuable tools or useless artifacts.” Spermatogenesis vol. 2,1 (2012): pp 1–5. doi:10.4161/spmg.19885.

Lin, Ann et al. “Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials.” Science Translational Medicine vol. 11,509 (2019): pp 1–4. doi:10.1126/scitranslmed.aaw8412.

Westhouse, Richard A. “Safety assessment considerations and strategies for targeted small molecule cancer therapeutics in drug discovery.” Toxicologic Pathology vol. 38,1 (2010): pp 165–8. doi:10.1177/0192623309354341.

Fitzmaurice, Christina et al. “The Global Burden of Cancer 2013.” JAMA Oncology vol. 1,4 (2015): pp 505–27. doi:10.1001/jamaoncol.2015.0735.

A special note of gratitude to Dr. Katherine Johnston for aiding me in my writing


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