Human Genome Project opens window to cancer therapies

By Noralyn Dudt & Aileen Tangonan MacAndrew

DNA ( deoxyribonucleic acid) is a molecule that contains the genetic code that is unique to every individual. Think of this code as an instruction manual for making all the proteins that form our bodies and help them thrive. The information code in DNA is hereditary which means it passes from parent to child. Because of this inheritance,  DNA also determines our traits  including how we are shaped and how similar we look to our parents and even grandparents. These traits coded in DNA will always get passed on from generation to generation. The DNA that determines heritable traits is found in the nucleus of every single cell in our bodies. DNA is made up of two intertwined strands linked together by pairs of building blocks, known as bases: adenine, cytosine, guanine, and thymine. Bases make up the rungs of the  DNA helix, the ladder-like double-stranded structure.  When a base joins the side of the ladder, a nucleotide is formed. When nucleotides pair with an opposite DNA strand, the ladder is complete. An A base always pairs with a T base, and a C base always pairs with a G base. By reordering these four bases in long DNA sequences, an infinite number of combinations is possible.

That is why there is a unique DNA sequence or code for every protein in our bodies, including those that determine our traits. For example,  a sequence of ATTTTG might instruct for blue eyes,  while a sequence of TTTTTG might instruct for brown.  By understanding how DNA is formed and knowing what unique DNA sequences encode each protein,  we can start understanding how DNA sequences affect how we function and how we look. This is because DNA is the instruction manual for all proteins that form our body and help it thrive.

The long chain of molecules that comprise DNA contains all the information necessary for the life functions of a cell—to develop, survive and reproduce.

Understanding that structure and function of DNA has helped revolutionize the investigation of disease pathways, assess an individual's genetic susceptibility to specific diseases, diagnose genetic disorders and formulate new drugs. It is also critical to the identification of pathogens that could harm our bodies. Venturing into new possibilities was finally possible when the Human Genome Project  was completed in 2003. It quickly  led to the growth of bioinformatics, a vast field of research  that has so much potential. The successful sequencing of human genome has been instrumental in solving some of the mysteries of many disorders in humans and allowed research scientists to venture  into new possibilities. It opened a window for scientists to work out which genes are mutated and gave them ideas for developing medicines. For example, it was found that certain breast cancers have a mutation in a gene called HER-2. As a result,  scientists were able to produce a monoclonal antibody. The discovery of associated gene provided scientists with the foundation for understanding the course of disease, treating disorders with synthetic DNA or gene products and assessing the risk for future disease.

Drugs that arose from  research such as trifluridine and tiparicil ( LONSURF) with bevacizumab gave hope to metastatic cancer patients who were previously treated for Colorectal Cancer. Approved  by the Federal Drug Administration on August 2, 2023, it provided the much needed relief for patients suffering from colorectal cancer which is a growth of rapidly dividing cells (mutated cells) arising in the epithelium of the colon and the rectum. It is the third most common cancer in men and women and the second leading cause of cancer-related death in the United States and worldwide. In the United States alone, there are approximately 153,020 estimated new cases of colorectal cancer in 2023, and 52,550 expected deaths. At diagnosis, the median age of patients is approximately 60 years old. The incidence of colorectal cancer is 1.4 x higher in men than in women. Certain risks factors for colorectal cancer are:  diet high in  animal fats and  processed meats; diet low in fiber; hereditary syndromes; lifestyle—smoking and alcohol use, not being physically active, diabetes, and age.

Patients who are diagnosed with metastatic colorectal cancer receive first and second line treatments with fluorouracil-based chemotherapy with oxaliplatin and irinotecan, vascular endothelial growth factor (VEGF-based therapy such as bevacizumab), and epidermal growth factor receptor (EGFR) -targeted therapies such as cetuximab or panitumumab for patients with RAS-wild type tumors.

Let us take a closer look at  what those therapies are.

VEGF-targeted therapies were initially developed with the notion that they would inhibit new blood vessel growth and thus starve tumors of necessary oxygen and nutrients.

EGFR therapies use medicines that bind to certain parts of the EGFR and slow down or stop cell growth. EGFR is a protein that is found on the surface of some cells that causes cells to divide when epidermal growth factor binds to it.

Bevacizumab stops the blood vessels from growing by blocking vascular endothelial growth factor (VEGF) from attaching to receptors on the cells that line the blood vessels.

Even after the disease progresses after the  first-and-second line of treatments, many patients are able to lead somewhat of a normal life. However, the next line of therapies would pose a challenge in extending  survival benefits. The latest data indicate that approximately 25% of patients treated with second-line go on to receive a third-line therapy and approximately 29% of patients treated with third-line go on to receive fourth-line therapy. However, patients who show progress after the second-line treatment are considered to have refractory disease—they no longer respond to treatments. Median overall survival for patients at second-line therapy  is approximately 10.4 to 16.2 months. As the main goal in Medicine is to lengthen a patient's life, some options are available, though not without risks:  oxaliplatin has potential but peripheral neuropathy (weakness, numbness and pain from nerve damage usually in hands and feet) and allergic reactions may add to an already existing health challenge.

How does the therapy work ?

Lonsurf is an orally-administered combination of trifluridine and tipiracil. Trifluridine works by stopping growth of cancer cells while tipiracil helps trifluridine by stopping it from being broken down by the body. When trifluridine undergoes intracellular, stepwise phosphorylation, it gets incorporated into DNA which can result in structural DNA damage and dysfunction. Moreover, the mechanism of action of trifluridine as an antiviral agent has not been fully elucidated, but appears to involve in the inhibition of viral replication. However, as trifluridine gets incorporated into viral DNA during replication, it leads to the formation of defective proteins and an increased mutation rate. In light of that, it is essential  that for trifluridine to do its work of stopping the growth of cancer cells, it must be  combined  with tipiracil. If not, it will undergo intracellular phosphorylation that would inflict  damage on structural DNA.

It is under this notion that clinical trials  called the C-TASK FORCE were conducted in Japan in 2014 It was a noncomparative study of trifluridine and tipiracil plus bevacimubab in 25 patients with mCRC (mutated colorectal cancer) refractory. As mentioned earlier, patients that are "refractory" means they no longer respond to treatments. Eventually, the C-TASK FORCE  evolved into the Sunlight study that investigated the efficacy and safety of LONSURF in combination with bevacizumab compared with LONSURF alone. The primary objective of the trial was to demonstrate the superiority of FTD/TPI plus bevacimubab over FTD/TPI monotherapy in terms of overall survival. (OS)

SUNLIGHT was the first and only phase 3 study with an active control in third line metastatic colorectal cancer that demonstrated statistically significant efficacy. The second trial that supported the rise of SUNLIGHT clinical data was undertaken in Denmark in 2017 and 2018. Collectively, these clinical trials provided a strong foundation for approval of these anti-cancer drugs. The clinical trials clearly demonstrated that these therapies are not only effective but also safe.

In the second series, we will explain how clinical trials are conducted and the multi-process of approving new drugs  by the Federal Drug Administration.

 

Aileen Tangonan MacAndrew and Noralyn Onto Dudt, both  of the Founding Team of the Claveria Reading & Mentoring EnClave in Claveria, Cagayan.

Aileen Tangonan MacAndrew, RN MSN, is a clinical nurse practitioner at the Hematology/Oncology University of California/Los Angeles Health.

Noralyn Onto Dudt tutored doctors and research scientists and edited their papers for scientific journals, before she retired in 2019.