Starving Brain Cancer -- In-Depth Doctor's Interview
Paul Mischel, M.D., from UCLA's Jonsson Comprehensive Cancer Center, explains how a new drug can help starve brain cancer cells.
What is glioblastoma?
Paul Mischel, MD: Glioblastoma is the most common form of primary brain tumor in adults. It's the most common cancerous tumor that arises from the cells of the brain itself and it’s one of the most lethal of all cancers.
What is the survival rate after a patient is diagnosed with glioblastoma?
Paul Mischel, MD: Patients with glioblastoma have a median survival of twelve to eighteen months, despite surgery, radiation and chemotherapy. The glioblastoma cancer cells are also very resistant to the traditional therapies of radiation and chemotherapy; tumors tend to aggressively recur after these treatments. Therefore, new treatment approaches are needed.
What is the new study all about?
Paul Mischel, MD: Cancer is a disease of the genes. That is, oncogenes have been firmly established as playing a central role in the development of cancer. Cancer is also a metabolic disease. Tumor cells use their energy and fuel sources in a completely different way than do normal cells. The novelty of this study lies in our finding a biochemical pathway that connects the altered genetics and the altered metabolism of these cancer cells, and which potentially opens the door for a new treatment strategy.
How are you targeting fatty acid?
Paul Mischel, MD: We’ve been studying the genetics of glioblastoma for a while, and one of the things that’s become clear, is that glioblastoma commonly contain a mutation and an amplification of a gene called the epidermal growth factor receptor (EGFR). This gene is amplified and/or mutated in almost half of patients, and this is significant because EGFR turns on signals to the cancer cell that tell it to grow when it’s not supposed to grow. Compelling evidence that EGFR amplification and mutation play an important role in glioblastoma development and progression, comes from looking at the genetics of the tumors from patients and from studying models that drive the formation of this cancer. Attempts to target the activity of this gene in the clinic have not led to the clinical responses that have been hoped for, despite the importance of this gene. We, and others, have shown that patients may not respond to drugs to target this gene because the tumor cells find alternate ways to keep on the signal that arises from this gene. In fact, there has been a real challenge to trying to understand how tumor growth promoting signals arising from this gene can be effectively blocked. One of the things that we begin to think about, as many others have also tried to think about, is that cancer is not only a disease of altered genes, but also a disease of altered cellular metabolism. Cancer cells change the way that they metabolize sugars, and turn them into fats in a way that’s completely different from normal cells. In fact, cancer cells have an increasingly enhanced demand for fats, and as they use fatty acids to do things like membranes in cancer cells, which are dividing these lots of membranes, they also use it to modify the signals that they make inside their cells, and also as an alternate energy source. We wondered whether EGFR also regulated the alternative metabolism of glioblastoma cells, and whether this could potentially be therapeutically targeted.
How do the cancer cells create energy using fat cells?
Paul Mischel, MD: Actually, the fat is not coming from fat cells. Rather, the cancer cells are manufacturing fats themselves, and unlike the body, in which the circulation to the body’s systems regulate fat in how energy balance is maintained, the cancer cells essentially create their own energy factories as well as their own fat factories in order to be able to make things like membranes, and create alternative sources. Trying to understand what the signals are and learning how the cancer actually creates the lipids, is a really important challenge. On one hand, people have been studying the genetics of cancer for a good 30 years, and the genetic landscape of cancer is being revealed at an incredible pace. It is also appreciated that cancer is a disease of altered cellular metabolism, but how the genetics link to the altered cellular metabolism and how that might illuminate new ways to treat the disease has remained elusive. This is the starting point for our work described here. We have been really interested in trying to shut off the signals in cancer patients. One of the ways that we can actually shut off the signal is where the signal actually meets the stimulus for altered cellular metabolism, so we became very interested in trying to understand how this process works.
Is there more than one type of glioblastoma?
Paul Mischel, MD: Glioblastomas are the highest grade (i.e. the most biologically aggressive type of tumor), and there appear to be two clinical routes towards its presentation. A minority of glioblastomas progress from a low-grade tumor and become a glioblastoma over time. In contrast, the majority of glioblastomas, especially in older adults, are a glioblastoma on initial presentation. Further, although these two types of glioblastomas look the same under the microscope, they are genetically different. Further, recent work suggests that there may be a number of genetically distinctive subtypes of this tumor; a theme common to many malignant cancer types.
How do you choose a treatment for glioblastoma?
Paul Mischel, MD: The standard approach to treatment is based on tumor pathology. However, as treatments are developed that target specific enzymes that are altered in the different genetic subtypes of glioblastoma, understanding the molecular and genetic lesions in a patient’s tumor may be critical for determining the best treatment. This is the critical challenge for personalizing therapy for cancer patients – trying to understand the molecular alterations in each patients tumor and using that to design a treatment plan. This study was designed to ask if tumors that contain EGFR mutations change tumor cell metabolism in a way that could be therapeutically targeted, potentially leading to a new treatment for patients whose tumors express these mutations.
How are you charting fatty acids?
Paul Mischel, MD: The first thing we did was to study tumor tissue from patients treated with a drug that blocks the epidermal core factor receptor. We asked whether blocking the activity of EGFR does that in fact regulate the metabolic pathways that lead to fatty acids in patients. In the process, we uncovered a critical link between the EGFR mutation and a master biochemical regulatory switch that the cancer cells use to make fatty acids, and we did so by studying patients in the clinic with a drug that blocks the activity of EGFR. We went about using cells in a dish to try to understand the signaling pathways by which they actually regulate fatty acid synthesis, and we looked at very carefully the pathways and found that the traditional genetic pathway that EGFR regulated was in fact, critical for regulation of fatty acid synthesis. The third part of the study was designed to ask if a cancer cell has this mutation, is it actually more dependent on this fatty acid synthesis and can it be specifically targeted? That was where I think the most important part of this study was. We found that if a cell actually has that EGFR mutation, it’s much more sensitive to blocking that fatty acid synthesis. What that means, is that you could potentially go to a patient to find out if they had the EGFR mutation, and if so, that patient’s tumor may be much more dependent on this metabolic pathway fatty acid synthesis and using drugs that block fatty acid synthesis could potentially produce a good response in those patients.
For the patients that are blocked, have you seen an increased life spam or the cancer go away or just stop growing?
Paul Mischel, MD: Let me clarify. The studies using a drug that blocks EGFR were done in patients; the studies using a drug that blocks fatty acid synthesis were done in mice. We hope in the future to try to determine whether blocking fatty acid synthesis this will help glioblastoma patients in a clinical trial.
What are the risks for the patient?
Paul Mischel, MD: There’s always risk to the patient when you’re treating a new drug. That’s why it’s very important to develop drugs that are very specific and go through the full clinical testing paradigms. We’re in a stage right now where that’s exactly what we’re doing, and we think that’s a critical part, because you want to make absolutely sure that you don’t harm the patients. There are drugs that have been designed to block the fatty acid’s synthetic machinery, but studies to test them in cancer patients are in very early stages. Considerable work needs to be done.
How does a patient get a hold of this drug?
Paul Mischel, MD: Drug development is a complex process. A drug must go through extensive preclinical testing, followed by a series of clinical trials to get FDA approval. We hope that a series of new agents that block this pathway will soon be available for testing in clinical trials.
Could this work on any other type of cancer?
Paul Mischel, MD: Yes. The epidermal growth factor receptor itself is mutated in a great many cancers; in fact, it’s one of the most common genes in all of human cancer. In addition, the pathways that it regulates to drive fatty acid synthesis are common to a number of different cancers. Therefore, there is reason to think that this approach may have potentially benefit for many cancer types.
What kind of cancer could this drug also treat?
Paul Mischel, MD: Lung cancer is the characteristic examples, and it’s very common cancer. Head and neck cancers contain EGFR mutations or amplification and there is actually quite a long list of cancers whose malignant behavior is actually driven by this gene. We studied different types of cancer cells in our study, and found that they too were equally sensitive to inhibition of fatty acids. The critical point here is this may identify a link between what's common to many cancers, and a discreet, targetable process that could be perhaps very effectively and therapeutically exploited in a number of different cancers. Our focus was the glioblastoma brain cancer, but this has an implication for a wide range of cancers.
What is the next step?
Paul Mischel, MD: The next step is to work with pharmaceutical companies to develop compounds that are selective, safe, non-toxic, and block the fatty acid synthetic process, and get them into clinical trials; particularly to patients who have this mutation. A second is a more of a biology focus to try to even further understand where along that biology pathway the cancer cells become dependent so we can develop even better compounds for blocking.
Is this the future of cancer research?
Paul Mischel, MD: Absolutely. This direction is one, of many important new opportunities brought about by a deeper understanding of cancer genetics. Advances in this field, coupled with studying the biology of cancer in models and integrating data with what is happening and what the drugs are doing to the biology of the tumor in patients is likely to be a very important direction for the future. Further, the role of cancer metabolism, and its link to genetics is likely to prove to be a fertile area for developing new ways to treat cancer. As a pathologist, I’m used to looking under the microscope in which we give a diagnosis, in which the cancer is based. The diagnosis is based really on what the cells look like under the microscope, but there is a recognition now that if you’re treating with things like radiation and chemotherapy that are relatively non-specific, it may not matter what the molecular composition of the tumor is. However, if you are trying to target specific components of signaling pathways and the metabolic pathways that are activated by specific cancer mutations, and you want to direct treatment with targeted inhibitors to the patients most likely to benefit, developing molecular tools to guide therapy is essential. That really is the essence of personalized medicine, so it means not just diagnosing the person with breast cancer, or glioblastoma, but diagnosing that person with a cancer containing suite of molecular alterations that are targetable, and this is a clear example, you’re taking a gene that’s diagnosable in a patient and linking it to a potential treatment strategy.
What made you go into this field and tackle this subject?
Paul Mischel, MD: I lost my father from cancer when I was 14, he was 51, and I came to really hate this disease. I felt that the way that we treat patients isn’t good enough. I decided to become a pathologist because I wanted to do something about cancer, and it was difficult for me to be in a clinic actually treating cancer patients, but I wanted to do something. I also trained in molecular and cell biology after I had trained in pathology, because I felt that there was information in the slides. The tissues that we look at in a cancer patient weren't being captured, and it wasn’t enough for me to be able to say that we’re looking and diagnosing cancer, and putting the person into a risk group. I wanted to get at and determine; could we get more information? Could we say how are you best going to treat that individual patient? not cancer patients in general, but that individual person, so I went about studying and gaining skills and tools, and learning from a number of marvelous people, and then into running a large and active lab to try to do exactly that. All of our work is about trying to understand, in that individual person’s tumor, what are the molecular lesions, what are the molecular targets, and how can you come up with a therapy that’s right for that individual person. In this case, it was by identifying a link between a particular gene, and a metabolic pathway fatty acid synthesis.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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