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| Emil Lou, MD PhD, Assistant Professor Masonic Cancer Clinic School of Medicine, Minnesota University Source:Oncology Frontier(肿瘤瞭望) |
Oncology Frontier(肿瘤瞭望): Pancreatic cancer is a highly malignant tumor with high heterogeneity. Molecular targeted drugs and immune treatment have no significant effect, which means the treatment of pancreatic cancer is extremely difficult at present. Could you talk about how we might overcome this dilemma?
Dr. Emil Lou: Pancreatic cancer worldwide still remains one of the most challenging cancers to treat unfortunately.
There are some properties unique to pancreatic cancer, and some that are very similar to other cancers.
It is considered a very heterogeneous disease in many ways, especially in terms of the mix of malignant cells and the stroma. The stroma is composed of a very diverse set of cells which include immune infiltration cells like neutrophils and macrophages. There is also activity leading to opportunity for angiogenesis, and vascular endothelial growth factor (VEGF) helps promote that in tumors that are hypoxic.
In pancreatic cancer especially, there are also pancreatic stellate stromal cells which form the base of the desmoplastic reaction. This causes a very dense tumor stroma matrix to form that is very difficult to penetrate. One of the key difficulties caused by such a dense matrixis that it prevents standard chemotherapy drugs from penetrating the tumor to work effectively.
A prime example I can give of that is the HALO trial here in the United States involving a drug called pegylated hyaluronidase. The aim of this enzyme is to break down the barriers that exist around pancreatic tumors.
The barrier includes hyaluronic acid which at the cellular level is a glycosaminoglycan. Hyaluronic acid forms a coat around the cells, forming a barrier, almost like a wall around the pancreas tumor.
For years we have been trying to overcome this problem. The enzyme hyaluronidase helps to break down the barrier and allow better penetration of chemotherapy.
Dr. Sunil Hingorani from the Fred Hutchinson Cancer Research Center provided some very exciting data from an interim analysis here at the meeting. The trial is an ongoing phase II trial that was launched based on phase I studies examining the safety of this drug in combination with standard chemotherapy (gemcitabine and nab-paclitaxel).
So far, progression-free survival by addition of hyaluronidase is over double that of a standard chemotherapy combination, gemcitabine/nab-paclitaxel, given alone (9.2 months vs. 4.3 months, in the population with hyaluronidase-rich tumors). We don't yet know the overall survival data but it looks extremely promising.
This is an excellent example of a two-armed clinical trial addressing whether addition of a rational drug improves patient outcomes.
Well-designed randomized clinical trials are required to move the field forward, and what we are trying to understand at the laboratory level is what molecular targets can be targeted with effective therapy.
Here at the ASCO Annual Meeting, we are hearing a lot about immunotherapies. The barriers around pancreatic tumors are still not allowing immunotherapies to work effectively at present but if we have a way to break down the barriers as with hyaluronidase, it might allow the immune system to attack the tumor in conjunction with standard chemotherapy.
Dr Lou: The theme of tumor heterogeneity is very prominent in pancreatic cancer. It is also prominent in many other different cancers, some of the most aggressive epithelial forms of malignancy. But among them, pancreatic cancer is one of the most heterogeneous diseases.
Not only is the tumor stroma a barrier to effective treatment strategies, but also the degree of mutation among the pool of malignant cells (tumor heterogeneity) may determine tumor growth and patient outcome as well. One of the prime examples is KRAS. KRAS is a GTPase that when mutated is permanently activated. This means it is always on and overexpressing the proteins that signal downstream pathways.
The implication of this is that there is the overproliferation of pancreatic cancer cells which makes them more invasive and at the clinical level in the patient, we see on CT scans that they grow locally and become unresectable.
We know that no more than 10-15% of all pancreatic tumors are resectable at the time of diagnosis, and that maximal resection of tumor would be the only chance for a cure of this very aggressive cancer.
Beyond that, these molecular signals stimulate pancreatic tumor cells to be more invasive and spread to other parts of the body as metastases. KRAS is thought to be present in 90-95% of all pancreatic cancers.
But what is coming to light, particularly at this meeting, is that it is primitive to say that tumors either do have KRAS or don't have KRAS mutations irrespective of whether we are talking about pancreatic cancer or colorectal cancer or others because there is actually a mix. This concept is called intratumoral heterogeneity.
Some cells will be KRAS wild types while other cells will be KRAS-mutated. One study presented in poster format at this meeting (Drs. Lennerz and Stenzinger, Abstract #4023) examined allelic ration of KRAS mutations in pancreatic ductal adenocarcinomas. In their examination of the ratio, the tumors that have more KRAS-mutated cells are more aggressive and the patients live for a shorter period of time.
If there is a smaller proportion, then they lived longer.
So there is quite a bit of difference and at the clinical level, we have not yet reached that point where we can select chemotherapy based on molecular features.
With next-generation sequencing and advanced digital PCR, there are molecular tools, which we did not have five or ten years ago, that are now at our disposal. The real task for researchers around the world is to investigate this and determine how we can more specifically tailor these sequencing therapies to individual patients.
Dr Lou: What is not yet known is what the differences are in pancreatic tumors between the Chinese population and Western populations, for example.
But we do know that one of the significant, and preventable, risk factors is smoking. Tobacco use can nearly double the risk for pancreatic cancer for those who smoke cigarettes versus those that don't.
Here at the ASCO Annual Meeting, we are hearing a lot about immunotherapies. The barriers around pancreatic tumors are still not allowing immunotherapies to work effectively at present but if we have a way to break down the barriers as with hyaluronidase, it might allow the immune system to attack the tumor in conjunction with standard chemotherapy.
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| ASCO 2015 McCormick Place, Chicago Photo: Oncology Frontier |
So with all of that in mind, the development of pancreatic cancer drug research is facing some formidable challenges. What is your opinion on this?
Dr Lou: The theme of tumor heterogeneity is very prominent in pancreatic cancer. It is also prominent in many other different cancers, some of the most aggressive epithelial forms of malignancy. But among them, pancreatic cancer is one of the most heterogeneous diseases.
Not only is the tumor stroma a barrier to effective treatment strategies, but also the degree of mutation among the pool of malignant cells (tumor heterogeneity) may determine tumor growth and patient outcome as well. One of the prime examples is KRAS. KRAS is a GTPase that when mutated is permanently activated. This means it is always on and overexpressing the proteins that signal downstream pathways.
The implication of this is that there is the overproliferation of pancreatic cancer cells which makes them more invasive and at the clinical level in the patient, we see on CT scans that they grow locally and become unresectable.
We know that no more than 10-15% of all pancreatic tumors are resectable at the time of diagnosis, and that maximal resection of tumor would be the only chance for a cure of this very aggressive cancer.
Beyond that, these molecular signals stimulate pancreatic tumor cells to be more invasive and spread to other parts of the body as metastases. KRAS is thought to be present in 90-95% of all pancreatic cancers.
But what is coming to light, particularly at this meeting, is that it is primitive to say that tumors either do have KRAS or don't have KRAS mutations irrespective of whether we are talking about pancreatic cancer or colorectal cancer or others because there is actually a mix. This concept is called intratumoral heterogeneity.
Some cells will be KRAS wild types while other cells will be KRAS-mutated. One study presented in poster format at this meeting (Drs. Lennerz and Stenzinger, Abstract #4023) examined allelic ration of KRAS mutations in pancreatic ductal adenocarcinomas. In their examination of the ratio, the tumors that have more KRAS-mutated cells are more aggressive and the patients live for a shorter period of time.
If there is a smaller proportion, then they lived longer.
So there is quite a bit of difference and at the clinical level, we have not yet reached that point where we can select chemotherapy based on molecular features.
With next-generation sequencing and advanced digital PCR, there are molecular tools, which we did not have five or ten years ago, that are now at our disposal. The real task for researchers around the world is to investigate this and determine how we can more specifically tailor these sequencing therapies to individual patients.
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| ASCO 2015 May 29-June 2, 2015 McCormick Place, Chicago |
Recent existing literature has reported on the effects of diet and nutritional factors on pancreatic cancer, but studies of the interaction between pancreatic cancer genes and the environment and diet are scarce in the Chinese literature. What is your opinion on this observation?
Dr Lou: What is not yet known is what the differences are in pancreatic tumors between the Chinese population and Western populations, for example.
But we do know that one of the significant, and preventable, risk factors is smoking. Tobacco use can nearly double the risk for pancreatic cancer for those who smoke cigarettes versus those that don't.
Obesity in the United States and the increased risk for diabetes is also a significant risk factor for developing pancreatic cancer. As other parts of the world adopt the so-called Western diet, there is an increased risk (particularly in Asia) for the development of pancreatic cancer.
Unfortunately there are still no clinically available screening tests for this type of cancer so we have to more effectively emphasize and address the potentially preventable causes of pancreatic cancer to reduce the cancer risk in individuals.
There are things we can't prevent in the development of cancer but we can avoid the use of tobacco, watch our diet and exercise appropriately. There are not copious numbers of randomized controlled trial data to say how long people will live or not live, but in many ways these recommendations follow guidelines that we follow for healthy living, including improved cardiovascular health.
For colon cancer though, it is known that patients who exercise 4-5 times per week, walking 30-45 minutes per session, tend to have a reduced risk of recurrence of their cancer. It would not surprise me if someone were to report similar findings for pancreatic cancer. It is really a good approach and common sense that exercise will be good for you and in conjunction with good nutrition, I think these will certainly be avoidable risk factors for pancreatic cancer as well as other cancers.
Reproduced from:
[ASCO2015]胰腺癌的分子和细胞异质性--Emil Lou教授访谈 2015/6/8 肿瘤瞭望 Video 微信公众号
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