Death of My Valentine
“Happy Valentine’s day. Thank you for the lovely flowers” said Victor on February 14th, 2023.
That was the last text I received from him before he passed. Victor, a 64+ year old male, was on hospice after failed chemotherapy and failed immunotherapy for metastatic gastric cancer. Gastric cancer is the fifth most common cancers and it is expected that 11,130 gastric cancer deaths will occur in the US in 2023. Unfortunately Victor is a part of that statistic this year.
With so many technological advances and scientific break throughs, how do therapies still fail?
No chemo drug can gaurantee a 100% success rate. The response rate for advanced gastric cancers is up to 60% for polychemotherapy (meaning multiple the use of chemotherapy agents) and even less for single agent therapies. While this is just the success rate of getting some sort of efficacious response from chemotherapy, most patients still develop drug resistance within a few months. By developing drug resistance, the cancer comes back and chemotherapy no longer works.
Chemotherapeutic resistance, whether intrinsic or acquired, is a multifactorial phenomenon associated with the tumor cells and the tumor microenvironment. Chemotherapy resistance could be acquired by drug efflux. ATP binding cassette (ABC), is a molecular transporter protein family that reduce intracellular concentration of drugs. This means that an efflux would increase chemotherapy agent concentration outside of the cell and redistribute the drug away from the tumor site. Drugs can also be inactivated causing resistance to chemotherapy. In the pre-clinical stage of drug development, scientists test pharmacokinetics — the concentration of a drug over time, through ADME. ADME stands for absorption, distribution, metabolism and excretion. When studying drug metabolism, there are phase 1 and phase 2 reactions. In phase 2 metabolic reactions, drugs are conjugated. Specifically, the body produces Glutathione S-transferases (GST) which is used to detox the conjugated proteins and inactivate chemotherapy drugs. Lastly, chemotherapeutic drugs on its own also cause DNA damage, induce cell death, or mutate the cell to escape cell death, increasing cellular resistance and allowing cancer cells to survive. While drug efflux, drug inactivation, or dysregulation of cell survival are three examples of cancer resistance, there are still more causes as well.
No immunotherapy can gaurantee a 100% success rate. Immunotherapy does not target the cancer itself. It targets the pateint’s own immune system to teach it to attack the disease. In most cases, immune based treatments stimulate T-cell response, a special immune cell in our body that fights pathogens and cancers. The relationship between a tumor and the immune system is extremely dynamic and there are a multitude of reasons that cause immunotherapy to fail. Tumors can develop mutations that prevent the T- cells from penetrating the tumor. Other mutations can also cause T-cells to no longer recognize the cancer cells as it was instructed to do by the immunotherapy agent, because the cancer cells have changed their membrane protein epitopes. This is the usual case for advanced cancers. Tumors can also change how they act to influence T-cell efficiency. It can turn down signaling pathways in the cells that normally stimulate T-cells and ultimately dampen anti-tumor response. an example of how this can work is presenting myeloid cells in the tumor to counter t-cell activity.
Each patient is unique in their own way. If each human physically looks different, imagine the diversity at a cellular and molecular level. High-throughput sequencing technology has increased the numbers of predictive markers and therapeutic target but there are still no solid biomarkers or predictive markers to treat resistance. Sometimes, even with all the scientific and technological advances, personalized treatments fail.
I gave Victor his flowers during his last consultation for a “second opinion” even though he had multiple consultations already clinging on for a hopeful option to survive. “Happy Valentine’s Day! I’m glad you liked them” I said.
References:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027022/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066028/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396490/#:~:text=Malfunctioning%20of%20antigen%20presenting%20cells,immunotherapy%20%5B10%2C14%5D.
