By Bill Thomas | November 1, 2024
Pediatric cancer research has made some very big strides in the last few decades, thanks in part to an ever-growing timeline of innovations funded by the generous donors of the Pediatric Cancer Research Foundation. Being the parent or guardian of a child diagnosed with cancer is never easy, of course, but there may at least be comfort in knowing that, thanks to the progress being made in ongoing research, pediatric cancer patients today have access to more treatment options than ever before.
Even still, there is one specific challenge that pediatric cancer researchers have yet to overcome. It’s a problem that, for many patients, could potentially render even the most promising cancer therapy ineffective.
That problem is the problem of cancer drug resistance.
What is Cancer Drug Resistance?
Cancer drug resistance, sometimes called “cancer treatment resistance” or simply “cancer resistance,” is a molecular change within cancer cells that makes them less susceptible to various forms of treatment. There are three main types of cancer drug resistance: primary, adaptive and acquired.
Primary cancer drug resistance, or “intrinsic resistance,” is when a specific type of cancer is resistant to a treatment even before the patient is administered it.
Adaptive cancer drug resistance, or “adaptive immune resistance,” is when a patient’s immune system successfully recognizes and attacks cancer cells, only for the cancer cells to adapt to protect themselves from the immune response.
Acquired cancer drug resistance is when a patient has been administered a treatment and experienced positive results. However, continued exposure to the treatment enables the cancer cells to gradually become more tolerant of the treatment, resulting in less positive results over time, as well as cancer relapse.
Finding New Answers, Asking Different Questions
So, what causes cancer drug resistance? Dr. Kyle MacQuarrie, a physician-scientist at the Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago, is just one of many researchers investigating the subject, albeit with a slightly different approach.
“The question [of how cancer cells become resistant] is a hard one to answer. A lot of studies have focused, very understandably, on seeing what a cancer that is already resistant looks like, then asking ‘How does this compare to a cancer that is not resistant?’” MacQuarrie explains.
“It’s not quite a ‘chicken or the egg’ dilemma, but it’s along those lines because you’re looking at the end result versus the starting point. The problem is that it’s not clear which changes are the ones that matter. We can see what has changed, but which changes are the ones that really drive the process of cancer resistance and which ones are just along for the ride?”
MacQuarrie is no stranger to pediatric cancer research. Since 2007, he’s published numerous papers investigating the biology of rhabdomyosarcoma (RMS), an aggressive form of skeletal muscle cancer that is the most common soft-tissue sarcoma in children. With funding from the Pediatric Cancer Research Foundation, MacQuarrie’s research through the Stanley Manne Children’s Research Intitute involves studying how the nuclear organization of RMS cancer cells contributes to gene fusions that reduce survival outcomes in patients with metastatic RMS tumors.
MacQuarrie’s interest in cellular organization plays a significant role in another avenue of research he’s pursuing: RMS chemotherapy resistance. MacQuarrie recently launched a new study, again with funding from the Pediatric Cancer Research Foundation. What is it about his new study that we at the Foundation find so exciting and so promising? In part, it’s MacQuarrie’s novel approach, his meticulous attention to detail and his desire to delve deeper into what exactly causes cancer drug resistance.
“Cellular organization is something that not a lot of people look at, especially when discussing chemo resistance. Most of the research is focused on looking at just the end result [of the cellular organization process]. That’s because that’s where the big changes are visible. It’s a lot harder to say ‘I’m going to look at all the little changes that make up this process.’ There could be 300 very tiny, very minor changes along the way and you have to sort through all of them,” MacQuarrie says.
“When we treat those cancer cells and they become resistant, is that a result of them changing and adapting under pressure from the treatment or is there something already there inside the cell that survives the treatment, which is then able to grow and proliferate and spread? These are some of the questions you have to consider. The reason I’m looking at the whole process is because I want to get a full understanding of how resistance works.”
Continuing the Conversation
Although cancer drug resistance continues to be a major roadblock for pediatric oncologists today, the future looks bright. Dr. MacQuarrie isn’t alone; all over the world, research is being done that could help bring us closer to our dream of a world free of childhood cancers.
Most recently, researchers at the Yale School of Medicine published a paper in the journal Science Immunology detailing their own investigations into cancer drug resistance. Specifically, the researchers wanted to find out why some cancers seem to have an intrinsic resistance to immunotherapy.
Using a genome-wide screen of more than 1,000 human proteins, researchers found that one particular protein, Phospholipase A2 group 10 (PLA2G10), was more commonly found in cancerous tissue – including lung cancers, pancreatic cancers and prostate cancers – than in normal tissue. Additionally, a lab-developed protein antibody proved effective in disabling PLA2G10 in mouse tumor models, instigating an immune system response that had previously lay dormant.
According to the paper, Yale researchers believe that PLA2G10 may be preventing chemokines from working properly, which would hamper the activity of anti-cancer T cells. It’s still too early to tell how accurate these findings truly are, but the Yale team members plan to continue their research. If additional experiments yield positive results, it could lead to a major breakthrough in cancer immunotherapy treatment.
Like Dr. Kyle MacQuarrie’s research, the Yale study is just one small part of a larger conversation surrounding cancer drug resistance. If you would like to participate in that conversation, consider donating to the Pediatric Cancer Research Foundation, so we can continue funding innovative studies like Dr. MacQuarrie’s. And don’t forget, to stay up-to-date with all the latest news shaping the future of pediatric cancer treatment follow the Pediatric Cancer Research Foundation Profectus Blog!
