Growing up in the ‘90s, I was a fan of Disney princesses and their gowns, which were often pink. Later this same color on a ribbon changed my view of the world, from princess’s gowns to cancer survivors. The pink ribbon is a symbol of breast cancer survivors.
Statistics say that 13 percent of U.S. women, roughly one in eight, are going to develop breast cancer in their lifetime. However, not all breast cancers will lead to death, especially if they are diagnosed at an early stage and also depending on the subtype, or molecular features, of the cancer cells. Cancer cells rely on structures called receptors, which are like small antennae on their surface that allow external signals to come inside the cell for communication. Other receptors inside the cell carry these signals further, some of which cause the cancer cell to divide and multiply. One effective way of killing the cancer cells is blocking specific druggable receptors.
My research is focused on a special subtype of breast cancer called Triple Negative Breast Cancer. A unique, and unfortunate, feature of this breast cancer subtype is that these cancer cells lack three important druggable receptors present in other breast cancer subtypes. Thus, targeting these receptors with drugs to stop cancer growth does not work for Triple Negative Breast Cancer.
Surgical removal of the tumor, chemotherapy, and radiotherapy are the most common treatments for Triple Negative Breast Cancer. But these cancer cells develop resistance sooner or later, as do many other types of cancers. Hence, researchers must find effective targets inside the Triple Negative Breast Cancer cells to stop their growth.
Scientists discovered many years ago that cancer cells depend on an enzyme called Fatty Acid Synthase for their survival. This enzyme manufactures new fatty acids by using other molecules in our body. Fatty Acid Synthase has several different functional domains for synthesizing new fatty acids. These newly manufactured fatty acids are then used by cancer cells for their own growth and to perform specific cellular functions that help cancer cells to survive.
Normal cells, on the other hand, use the dietary fats that we normally eat and do not need Fatty Acid Synthase.
Therefore, if I can discover a drug that only blocks Fatty Acid Synthase, cancer cells will die with little toxicity to normal cells. This is because most, if not all drugs have more than one effect on cells in our body, which we call side effects. An important consideration in this type of research is to keep toxicity low to normal cells.
How can I find such a targeted drug? Drug repurposing is currently a hot topic in the field of biomedical research. This is a novel approach that can often find new uses of existing FDA-approved drugs, in my case, by looking for new effects on cancer cells. Our lab has discovered that drugs that are used for gastric acid reflux can make a likely outcome of specific cancers better by inhibiting Fatty Acid Synthase.
Of many drugs tested, lansoprazole has been shown to have the best effect against a pancreatic cancer cell line. Lansoprazole is broken down by the liver into another chemical called 5-hydroxylansoprazole sulfide (5HLS). A previous student in my lab tested both lansoprazole and 5HLS against Triple Negative Breast Cancer cell lines and discovered that 5HLS kills more cells than its parent drug lansoprazole.
5HLS differs from lansoprazole in its molecular structure in two positions. This prompted me to think that if new analogs of lansoprazole are made with slight modifications in critical molecular positions, it might make these new analogs better cancer drugs with less toxicity to normal cells.
With this in mind, I started my drug discovery project by having different lansoprazole analogs synthesized by the medicinal chemist in our research lab. My research project is to identify a new lansoprazole analog that can kill Triple Negative Breast Cancer cells at a low concentration. Identifying a lansoprazole analog that can inhibit Fatty Acid Synthase at a lower concentration is important since lower concentrations would reduce toxic effects the analog might have on normal cells.
I grow Triple Negative Breast Cancer cells on culture plates and then add my lansoprazole analogs to see which one has killed the most cancer cells with the lowest concentration. I also perform chemical assays to determine which part of the Fatty Acid Synthase molecule this analog is inhibiting.
All of this information will help to figure out the mechanism of action of lansoprazole analogs to block Fatty Acid Synthase. This information is important to determine if one of these analogs can be used to treat Triple Negative Breast Cancer without potential side effects on normal cells. I will also test these analogs in normal cells in culture because it is also important to directly test if normal cells are affected by my most potent analogs.
With this approach, I plan to contribute to the field of cancer treatment, strengthening the promise of the pink ribbon, to survive.
Shreya Ganguly is a Ph.D. student in the Cell and Cancer Biology Track in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. Shreya is conducting her research in the laboratory of Dr. Jian-Ting Zhang. For more information, contact Shreya.Ganguly@rockets.utoledo.edu or go to utoledo.edu/med/grad/biomedical.
First Published April 3, 2023, 12:00 p.m.
