When cells kill: understanding cancer
Most of us will be affected by cancer in our life, whether we have cancer ourselves or have a family member or close friend diagnosed with cancer. Although the scientific community has made great strides in the diagnosis and treatment of various cancers, we still have a long way to go.
Even though we often refer to ‘cancer’ as a singular entity, the term encompasses several hundred different diseases. Cancer describes diseases characterized by uncontrolled growth and division of abnormal cells in the body. The similarities between cancers generally end there. Different cancers accumulate different mutations over time. Even cancers in the same tissue can look biologically and genetically different. Deciphering cancer is like a hard jigsaw puzzle.
Thanks to advances in technologies, tumor analysis, and drug development, over the past decade, scientists have gained more insight into cancer formation, progression, and therapy. Listen to Tiny Expeditions, Season 3, Episode 5, “When cells kill: understanding cancer,” to learn about cancer research and how scientists use cutting-edge technology to help diagnose, treat, and hopefully even prevent cancer.
Behind the Scenes
HudsonAlpha faculty investigator Sara Cooper, PhD, focuses her research efforts on understanding mechanisms of cancer pathology, progression, and chemoresistance in an effort to help personalize cancer diagnosis and treatment. The lab currently focuses on pancreatic, ovarian, and breast cancers.
Cooper and her longtime clinical collaborator Rebecca Arend, MD, an assistant professor in the University of Alabama at Birmingham (UAB) Division of Gynecologic Oncology along with associate scientist in the Experimental Therapeutics Program at the UAB Comprehensive Cancer Center, have been working together for several years to identify new drugs, new drug targets, and new combinations of drugs to overcome current ovarian cancer treatment limitations.
In a recent study, the group found that many patients had tumor gene expression profiles associated with known targetable pathways. In addition, they identified several promising biomarkers of response to treatment and new therapeutic targets.
Although many cancers are initially susceptible to chemotherapy, over time, they can develop resistance and stop responding to the treatment. For patients with cancers where chemotherapy is their last or only option, learning their cancer is resistant to treatment is devastating news. As we heard in the episode, Cooper’s lab is focused on identifying genes and mechanisms critical to the development of chemoresistance and establishing reliable methods for detecting them in clinical samples.
One way in which the group is achieving this goal is using genome-wide CRISPR screening methods to identify genes associated with chemotherapy resistance in pancreatic and ovarian cancer. CRISPR gene-editing technology can individually activate and knockout each gene in the genome in cancer cell lines to identify genes whose loss or gain of expression can alter sensitivity to common chemotherapies.
Using these screens, Cooper’s lab identified several gene pathways associated with drug resistance in pancreatic cancer. The team narrowed in on a gene that codes for an enzyme called histone deacetylase 1 (HDAC1), involved in chromatin remodeling. High expression of HDAC1 is also associated with poor patient prognosis in pancreatic cancer. By overexpressing HDAC1 in cell lines, the team discovered that it regulated genes that are part of the epithelial-to-mesenchymal transition, a pathway known to be involved in multi-drug resistance.
As part of her graduate work, PhD candidate Carter Wright (pictured right) is continuing to pursue additional studies to identify key genes and pathways downstream of HDAC1 that might represent novel therapeutic targets themselves. HDAC inhibitors have been used in treating some cancers and are being explored in clinical trials for pancreatic cancer. However, since histone deacetylases are involved in many functions in the human body, the inhibitors can induce unwanted side effects. Carter hopes to look at all the genes regulated by HDAC1 to see if one or a small subset of them are driving the resistance.
Several genes are well-known for increasing a person’s incidence of developing cancer in their lifetime, like the BRCA1/2 genes in breast cancer. More than 50 hereditary cancer syndromes have been discovered caused by changes in specific genes that can be detected through genetic testing. Several gene variants not associated with a hereditary condition have also been linked to increasing a person’s chance of getting cancer. Often, families with a high incidence of cancer will opt to have genetic testing performed on family members to identify the cause of the increased incidence.
Some families with a high cancer incidence do not carry changes in any known cancer predisposition genes. Cooper and her lab aim to find new genes that predispose individuals to cancer through a collaboration with the local Huntsville clinic Clearview Cancer Institute. During a pilot project, the team will collect DNA samples from 10 individuals with a strong family history of cancer at a young age. These individuals will have had cancer screening that did not return a cancer predisposition gene. By performing whole-genome sequencing on the samples, the team hopes to find new cancer predisposition genes. The pilot will serve as a proof of concept that the team can collect, sequence, and analyze the patient’s genomes.
Season 3 of Tiny Expeditions is made possible through the support of our sponsors:
Sarah Sharman 00:00
Season Three of Tiny Expeditions is made possible through the support of our sponsor EBSCO Information Services, the leading provider of online research content, search technologies and workflow tools, serving public libraries, schools, academic institutions, corporations and medical institutions around the world. Proudly delivering information access for researchers at all levels, online at ebsco.com. That’s E-B-S-C-O dot com.
Chris Powell 00:33
Welcome to Season Three, Episode Five. Today’s episode is all about cancer.
Sarah Sharman 00:40
I’m Dr. Sarah Sharman, here to help you understand the science.
Chris Powell 00:43
And my name is Chris Powell. I’ll be your storytelling guide for today. Take just a moment and look around. Like don’t make it weird, okay, but take a moment look around and if you’re driving take precautions there as well. But if there are people around you think about this, the CDC tells us that one in three of us will be diagnosed with cancer at some point in our lifetime. It’s a whole lot of us. And for the two of the three that are not diagnosed, chances are we know someone who will be diagnosed, or we’re going to be affected by cancer. We’re all aware of cancer, it affects us all.
Sarah Sharman 01:19
Although one in three of us will be diagnosed with cancer in our lifetime, it doesn’t mean that one in three of us will die from cancer. Advances in technology have led to new and improved screening methods and treatments that just weren’t around 50 years ago. But we still have a long way to go. There are many questions that remain unanswered. Like how do we overcome drug resistance and recurrent cancer? Will we ever be in a place to prevent cancer in the first place? Can scientists develop tools to quickly identify and target mutations in cancer cells? Today, we will hear the answers to some of these questions and learn how technologies that were once scary and unknown to us like gene editing can help scientists find answers to big questions in the cancer field. Here to help us answer these questions is Dr. Sara Cooper, a faculty investigator here at HudsonAlpha.
Sara Cooper 02:08
My name is Sara Cooper. I am a faculty investigator here at HudsonAlpha. And I also am the director of our Information is Power program. So, my lab is interested in using genetic and genomic technologies to understand cancer and help understand how we can better treat cancer. And my role with the Information is Power program is to provide information about genetic testing that can inform people about their risk for cancer and allow them to get appropriate screening.
Sarah Sharman 02:36
Before we go any further into the episode, we need to define our terms. What exactly is cancer?
Sara Cooper 02:42
I think the easiest way to describe cancer is our bodies are made up of trillions of cells. And normally they divide or reproduce at a particular rate depending on the tissue that they’re in. And cancer cells, essentially are cells that develop the ability to divide or reproduce more quickly than they need to, which leads to the formation of essentially small clumps of cells that are different than the other cells around them. And through this process, they not only develop the ability to grow and divide more quickly, but they change a lot about how they behave. They acquire mutations or changes in their DNA. Pretty much almost everything about how a normal cell function changes through the process of a tumor developing. And so those tumor cells then have different ways that they produce energy and use energy. They grow and divide more quickly. They are no longer able to go through sort of the quality control process that normal cells go through to make sure that they’re healthy after a new cell has been provided or has been made. And they also can evade or get away from normal cells that would and processes that would identify those cells as being bad for the body and that our immune cells, for example, would recognize them and be able to kill them. So, all that together leads to the formation of a set of cells that grow and divide and eventually cause all sorts of problems, especially if they ultimately leave the site that they originated from. So, if it’s a breast tumor, they leave the breast tissue and start to invade other parts of the body that’s in particular, where they become very difficult to get rid of and problematic and cause major health problems for the patients.
Sara Cooper 04:45
It doesn’t only affect the person that is sick, you know, and that’s true for a lot of diseases, of course, but it really is a difficult disease to treat even when it’s successfully treated. It’s a long time, it’s a long process to go through. My sister-in-law went through this process last year. And it was, I mean, she’s doing well now. But it was truly a full year of just being at the doctor and going through treatments and surgeries, and even when it’s going more or less as planned, it’s still really hard. So, from the perspective of, you know, a personal perspective, it’s a disease that is very, you know, it takes away your ability to do the things that you really want to do. And, and it also impacts, you know, your family in the sense that, you know, kind of have to put a little pause on your life and everything that you would normally be doing in order to take care of yourself, of course.
Sara Cooper 05:50
But from the perspective of research, I think it’s also a challenge. You know, cancer, we talked about this, it’s not just one thing. There are dozens of different primary sites, but even within those, there are so many different subtypes of disease. There are all these different treatments that could be selected, depending on the current health of the patient, depending on the molecular markers that are present in the tissue. And sometimes it’s not a regimented, ‘oh, if you have this cancer, you get this treatment,’ you know. There’s a lot of information that goes into making that decision. And at the end of the day, there’s still not always just one right answer. The physician and their patient have to decide for themselves what’s the best option for us right now, given the information that we have, and sometimes you find out that was the right choice. And sometimes you wonder if it wasn’t. And so I think that’s why the research is important because we really want to be able to inform that decision as well as possible.
Chris Powell 07:00
If you or someone you know has undergone a classical treatment for cancer, like radiation or chemotherapy, you’re definitely aware of the side effects of those treatments. Things like hair loss, a weakened immune system, change in taste and appetite, loss of energy. And the side effects are pretty severe. And the reason for that is because to kill the cancer, well we in essence have to introduce a poison to our system.
Sara Cooper 07:23
The sort of classic treatment protocols for cancer includes radiation, which basically uses the idea that inducing damage to tissue sort of can, in particular, target cells that are growing quickly, like cancer cells. Obviously, radiation in general is not a healthy thing for cells, but it’s particularly unhealthy for tumor cells that are quickly dividing. A lot of classic cancer treatments use that strategy, essentially, how can we kill cells that are dividing quickly more efficiently than cells that are dividing at a normal rate? So, a lot of what I would call like cytotoxic chemotherapy is the classic chemotherapy drugs that have been used for many of them for decades to treat cancer, also use that general strategy of trying to induce damage to those cells, whether it’s DNA damage or other forms of damage to those cells, causes cancer cells to die more easily. But that’s also why certain side effects happen. Issues with skin and causing nausea and intestinal problems because those cells are also normally dividing quickly in our body. So those treatments can be difficult for patients to endure, especially if they’re already sick and unwell.
Sarah Sharman 08:59
Cytotoxic treatments can’t differentiate between cancer cells and healthy cells. Thanks to large-scale cancer genome sequencing projects, scientists have identified ways to strictly target cancer cells.
Sara Cooper 09:11
Other treatments that have been developed more recently sort of fall into the broad category of targeted therapies. So those drugs generally have been developed to target a particular feature of a tumor cell that is either never or rarely found in normal cells. And so, I mentioned earlier HER2+ breast cancer patients. There are a subset of breast cancer patients that have a particular receptor or protein that is on the surface of those tumor cells. And we have a drug called Herceptin that can actually identify those cells and essentially kill those cells, remove them, and then they’re removed from the body. It’s something that normal cells wouldn’t have, and it’s very effective and has dramatically improved how patients with that particular type of cancer far with their treatments.
Sarah Sharman 10:08
The immune system protects our bodies from outside invaders like bacteria, viruses, and toxins that can cause infection, illness, and disease. In addition to foreign invaders, the immune system also recognizes cancer cells as different and tries to prevent or slow cancer cell growth. However, cancer cells use many different techniques to hide from the immune system. A newer treatment called immunotherapy tries to combat cancer’s evasion tactics.
Sara Cooper 10:35
Immunotherapy, essentially, is a way of activating our own immune system to encourage it to recognize tumor cells in our body and hopefully promote the elimination of those cells from the body. And so, there’s even within immunotherapy, a lot of different ways of doing that, and everything from drugs that are relatively straightforward that just sort of activate immune cells to things that are very targeted and even specifically developed for an individual tumor in an individual person. Those are kind of cool and exciting to think about, but also really expensive and difficult.
Sarah Sharman 11:13
So, I have a family member who is currently going through treatment for breast cancer. She received radiation, chemotherapy, and immunotherapy. And it turns out she’s not alone in receiving a combination of different therapies.
Sara Cooper 11:26
So, the initial decision to treat patients, especially with an aggressive form of cancer, with multiple drugs, is partly to avoid resistance. So it’s easier for a tumor cell to develop resistance to one drug than to multiple drugs. So, the idea is if you treat with multiple drugs from the beginning, you might be less likely to have a resistant tumor develop. But nonetheless, it does happen. In ovarian cancer, one of the cancers that we study, that’s a common challenge when patients have a recurrence, which does happen to somewhere around three-quarters of patients ultimately have a recurrence. And it can be months later, but can also be years later, it can be a decade later. But when that happens, typically, the drugs that we have don’t work anymore. And so, patients are left with very few options. They can enroll in clinical trials, which is often what clinicians recommend because that’s an opportunity to try drugs that haven’t been fully approved yet but do have evidence that they may work at least for some patients. And so yeah, it’s really a puzzle for researchers, but of course for physicians and their patients to try to figure out for any given person with a particular tumor type what set of treatments is the most likely to work.
Sarah Sharman 12:53
There are many cancer treatments, but they don’t magically appear out of thin air. A lot of hard work goes into developing them. Let’s go into the lab and learn about one such pipeline going from target discovery to drug development.
Chris Powell 13:06
Okay, so are you Carter?
Carter Wright 13:08
Chris Powell 13:09
Excellent. It’s good to meet you. Right. So, first of all, this lab is amazing. This is all the Cooper lab? This is large.
Carter Wright 13:17
It is. So, what you see right here is Dr. Sara Cooper’s lab. And on both sides of us are Dr. Richard Myers and Dr. Nicholas Cochran, who both focus on neurodegenerative disease.
Chris Powell 13:30
Excellent. So, tell us about your work. We’ve heard some really cool things here.
Carter Wright 13:34
Yeah, so my work focuses on pancreatic cancer and using CRISPR to express more or less of a gene to try to understand which genes have the potential to give pancreatic cancer cells resistance to chemotherapy.
Sarah Sharman 13:51
Very cool. So, have you found anything exciting?
Carter Wright 13:54
Yeah. So, we use this CRISPR technology. And through that, we identified a family of genes that are associated with drug resistance and pancreatic cancer. And one of those genes is HDAC1, which regulates genes important for drug resistance, cancer progression, and tumor suppression, making it a strong candidate as a drug target. And so, we showed that inhibiting HDAC1 sensitizes these pancreatic cancer cells to chemotherapy treatment.
Chris Powell 14:27
So how long have you been working on HDAC1?
Carter Wright 14:31
I’ve been working on HDAC1 since 2019.
Sarah Sharman 14:36
And you’re a graduate student here in the lab?
Carter Wright 14:38
Yes. I am a PhD candidate in my fourth year.
Sarah Sharman 14:44
So, I’m a cancer researcher by training, and you know, I’ve heard of HDAC1 inhibitors before. Can those be useful, or are there problems with them?
Carter Wright 14:53
Yeah, so commercial HDAC inhibitors in the context of pancreatic cancer they’re not specific, and they tend to have toxic side effects for patients. And so, this motivated our current study, where our goal is to understand how HDAC1 overexpression contributes to drug resistance and identifying genes that HDAC1 regulates that might lead to these alternative treatments, strategies, and other genes that we could target for patient treatment.
Chris Powell 15:24
So, the talk of this research is pretty cool. It’s actually kind of mind-blowing if you think about it. And Sarah, I think a lot of us have this misconception, when we hear this kind of cool research happening that we’re just going to take this and immediately go and apply it to therapies or two forms of early treatment, that’s really not the case, right? It’s much more involved in that.
Sarah Sharman 15:46
Right. So, on average, getting a potential drug candidate from the lab to the pharmacy takes about 10 to 15 years. And that’s if your target is successful in the first place. As someone who used to work in research, I can tell you there are many times when I found an exciting target, and then eight experiments later, I realized that I hadn’t hit the nail on the head. However, new technology is making these early stages go by quicker, and that’s really speeding up the entire development process.
Chris Powell 16:14
So new technologies are speeding up the process, but also new models are helping to speed this process up as well. I mean, here it HudsonAlpha it was based on the model of co-locating researchers with biotech companies so that you can take the research and I know a lot of people get frustrated, because research is happening all around, and papers are being generated. And then the question is, well, what do we do with these papers, right? Well, we still want to produce the papers. But then those papers can be taken across the street, or across the hallway, even, to a biotech company who can now take this research and commercialize it and bring it to the masses that much quicker. So new technology, new models, but then there’s also new forms of collaboration that can speed this up as well.
Sarah Sharman 16:57
So, Dr. Cooper’s lab recently started a new collaboration with a local cancer institute. And this collaboration is not only going to help current patients, but it might also identify new drug targets and genes for early screening that could help future patients.
Sara Cooper 17:12
Sometimes we encounter families who come in, and they have extremely strong family histories of a particular type of cancer. So, I’ll use breast cancer as an example since some of our patient families have been in that boat. We’ve had a participant in one of our studies who has had breast cancer herself and has two sisters that have had breast cancer. They all were under 50 when they were diagnosed, and one of them actually had breast cancer in both breasts, which is another sort of red flag of this is likely a genetic cancer because cancer has some aspect of randomness. So sometimes, it just happens. But when it happens twice in the same person, you start to get suspicious that a genetic factor might be involved. And so, this particular person has gone through standard clinical genetic testing, and it all came back negative, meaning they couldn’t find anything in her DNA in any of the genes that we know about that would explain why she and her family had this high incidence of breast cancer. So, we’ve started a study with Clearview here in Huntsville to partner with their genetic counseling group. And Amy George in particular has been an important part of this study. And she’s helping us identify patients and their families who sort of sound like the one I described. And we are using whole genome sequencing to try to determine whether there are other places in the genome that maybe we don’t know about yet, or that maybe we’re suspicious about but not so sure. And see if we can identify any new places in the genome that might be important for risk that haven’t been seen yet.
Chris Powell 19:00
We want to thank Dr. Sara Cooper for giving us this glimpse into cancer research today. But we want to be honest with you and kind of pull back the curtain a little bit here. As we were talking with Dr. Cooper, we discovered that not only is this research groundbreaking and just amazing to hear, but there’s actually something else that we didn’t even have time to get to that you really need to hear about.
Sarah Sharman 19:21
Hopefully, you’ve gleaned from this episode that treating and diagnosing cancer are important. But the end goal has always been to prevent cancer in the first place. Early detection and screening are a crucial part of preventing cancer. And that doesn’t just mean finding genes that predispose people to cancer. That also means making the screening widely available to everyone.
Chris Powell 19:41
So, join us for that very special episode coming your way very soon. But for today, thank you for joining us for this tiny expedition into the world of cancer research.
Sarah Sharman 19:52
Next time we’re talking about rare diseases and the role genomics plays in ending patients and diagnostic odysseys. You’ll also hear about a family’s journey with rare disease and how their experiences led to becoming advocates for other families with trisomy 18.
Chris Powell 20:08
Tiny Expeditions is a podcast about genetics, DNA, and inheritance from the HudsonAlpha. Institute for Biotechnology. We’re a nonprofit research institution in Huntsville, Alabama.
Sarah Sharman 20:18
We’ve got a campus full of scientists doing public research alongside companies developing products and services, all with one aim to translate genomic discoveries into real-world applications that make for a healthier, more sustainable world. That’s everything from cancer research to agriculture for a changing climate.
Chris Powell 20:35
If you find this podcast interesting, please rate, review, like, and subscribe on the podcast app of your choice. And tell somebody you listened to this interesting little story about genetics. Knowledge is always better when you share it.
Sarah Sharman 20:47
Thanks again to our sponsor, EBSCO Information Services. And thanks to you, our listeners, for joining us.