Speaking of pancreatic cancer(from valuation thread) and prostate(Ian's last post), I found the below which was delivered at ASCO 2004 and because no material progress on this dreadful cancer..
Presidential Symposium Provides Overview of Need for Progress in Diagnosis and Treatment of Pancreatic Cancer
Last Updated: June 08, 2004
The Presidential Symposium, “Progress and Promise in Pancreatic Cancer,” presented on Sunday, reflected both the passionate interest of Margaret A. Tempero, MD, and the growing recognition that there is a need for more rapid progress in the diagnosis and treatment of pancreatic cancer. In her opening remarks, Dr. Tempero cited a February 2001 report from the Pancreatic Cancer Progress Review Group (PRG), for which she served as Co-Chair, which revealed serious challenges to such progress. “We found gaps in every area we looked at, including developmental biology, cancer biology, animal models, risk and risk management, early detection, host-tumor interaction, therapy, and assessment of therapeutic benefit,” she said. “We even found gaps in training.”
The most serious gap, according to Dr. Tempero, is the lack of funding for pancreatic cancer-specific research. Citing a National Cancer Institute report on funding for the five cancers with the highest mortality rates, she pointed out that, although more people die from pancreatic cancer than from prostate cancer, only $1 is spent on pancreatic cancer for every $100 spent on prostate cancer.[ this is sobering The news is not all bad, though. Dr. Tempero noted that, since the release of the PRG report, there have been important advances in the understanding of animal models, sporadic and familial risk, tumor microenvironment, and new pathways required for tumor maintenance. “There has been enormous progress, in spite of the fact that there isn’t as much funding as we’d like,” she emphasized.
Following Dr. Tempero’s opening remarks, Ronald A. DePinho, MD, of Harvard Medical School, began the discussion with an update on developments in research related to the biology of pancreatic cancer. “Pancreatic cancer is an enigmatic disease about which we have precious little information,” he said. “If we are to do something about this disease, we really have to understand its genetics and biology.” If, as Dr. DePinho suggested, targeted therapy is the key to finding the ultimate cure for any cancer, then the search for cures begins with the identification of genes that drive the disease and the genes that are rate limiting to the cancer process. The next challenge becomes the validation of the genes that are truly important and the identification of their roles in the pathogenesis of progression. Lastly, investigators must decide which genes to move forward to lengthy trials. According to Dr. DePinho, based on what is already known and some of the work that is currently being done, “it is possible to increase by a factor of 10 the number of genes validated.”
After outlining some of the steps necessary to identify human pancreatic cancer genes, Dr. DePinho provided an overview of all previously reported regional gains and losses, the discovery of many novel recurrent regions of amplification and deletion, and the selection of 64 focal minimal common regions (MCRs) of recurrent copy number change. “The issue now is validation and prioritization,” he said. “Just because a gene is mutated in cancer doesn’t mean that gene is important for tumor maintenance. We believe that among the modalities that are needed to validate genetic lesions are the development of refined model systems that allow you to ascertain whether or not that gene is important or what function that gene might have in the development.” To illustrate that point, he described a mouse model with stereotypical presentation that provided the opportunity to assess additional genetic events.
In conclusion, Dr. DePinho noted, “If we are going to do anything about this disease and not simply throw compounds into clinical trials and hope that they work, we need to understand more about the genetics of what drives sporadic tumors as well as what conditions individuals for increased risk. We need to understand how those genes commandeer the biology of these cancers. We need model systems for a variety of needs, and we need to identify individuals with this disease relatively early in the course of the disease.”
Murray Korc, MD, of Dartmouth-Hitchcock Medical Center, focused on the fact that pancreatic cancer is characterized by an intense stroma formation that often surrounds the cancer cells with fibroblastic elements and marked collagen deposition. “In the past, it has been presumed that this was a relatively inert environment that encapsulates the cancer cells,” Dr. Korc explained. “However, work from many different laboratories in recent years has revealed that the stroma contains cellular elements that produce and store growth factors and it can serve as a reservoir that releases growth factors, thereby enhancing pancreatic cancer growth.”
As an example, Dr. Korc cited vascular endothelial growth factor (VEGF), which is produced by stromal elements in significant amounts. VEGF is a potent stimulator of blood vessel cell proliferation, he explained; consequently, the cancer cells can elicit the proliferation of endothelial cells and form an aberrant microvascular network that brings nutrients and oxygen to the cancer cells. Sequestration of VEGF by a recombinant protein called “VEGF trap” can reduce tumor angiogenesis, thus preventing tumor growth and interfering with its potential to metastasize. Although it is too early to be certain, Dr. Korc said that there is some convincing evidence that VEGF trap could be used to treat patients with pancreatic cancer and to prevent disease recurrence following surgery. “Effective targeting of VEGF has considerable therapeutic potential in this disease,” he concluded.
Gloria Petersen, PhD, of the Mayo Clinic Cancer Center, presented information on progress in defining and understanding the risk for pancreatic cancer. Although a number of risk factors have been identified and there is a great deal of ongoing research related to all risk factors, Dr. Petersen confined her discussion to three of these factors: family history, smoking, and age. “These are three very identifiable risk factors that clinicians can look at,” she said, adding that they are also all intertwined.
According to Dr. Petersen, an abundance of data indicates that first-degree relatives of individuals who have had pancreatic cancer have a two to three-fold increased risk of the disease. She cited a prospective study by Klein et al that involved 5,179 individuals, including 853 families who were followed for a total of 14,128 person-years [Cancer Res, 2004; 64:2634-2638]. “Among the family members who did not have cancer at baseline, there were 22 incidents of pancreatic cancer reported, and 21 turned out to be in blood relatives,” Dr. Petersen reported. “Unfortunately, 21 of the 22 [had] metastatic disease. This is where a lot of work is needed and why we’re doing this,” she said. Nineteen of the eligible cases in this study were used to determine the familial risk, which was estimated at nine percent in these individuals, compared with the general population.
In discussing smoking, Dr. Petersen commented that it has been identified as a risk for pancreatic cancer, and there is evidence that it interacts with family history. “When you actually look at the interaction of nonsmokers versus smokers there is an increased risk,” she explained. “The Klein study found that the risk factor was 19-fold if a family member was a smoker.” She added that other data indicate that cancer develops one decade earlier in smokers than in nonsmokers.
On the relationship between age and pancreatic cancer, Dr. Petersen commented that the presence of genes associated with pancreatic cancer seems to be related to an earlier onset of pancreatic cancer. She cited a study that found that an estimated 17% of familial pancreatic cases involved carriers of germline mutations of the BRCA2 gene [Murphy et al. Cancer Res, 2002; 62:3789-3793]. A second study found that at least 12% of familial pancreatic patients appear to be carriers of the BRCA2 gene [Hahn S. J Natl Cancer Inst, 2003; 95:214-221]. “Interestingly, in both these studies there was no obvious hereditary breast or ovarian cancer appearance, so the what we’re looking at is BRCA2 acting in a different pathway and causing familial pancreatic cancer,” Dr. Petersen said. “This story is still in development.”
“The physiologic effects of metastatic disease kills most patients with pancreatic cancer,” said James Abbruzzese, MD, of M.D. Anderson Cancer Center, in opening his discussion of the opportunities for therapeutic intervention in pancreatic cancer. “We have made little progress in developing effective therapy for patients with metastatic cancer. We’ve really got to do better, and we’ve got to take a somewhat different approach to this disease.”
With that in mind, he suggested the need for new approaches that combine science with bold clinical investigation. He identified three questions critical for such an approach.
•What are the molecular properties that characterize pancreatic cancer?
•What are the early molecular alterations that cause the disease we recognize as pancreatic cancer? Can they be targeted for therapy?
•How can we exploit novel molecular features as targets, and what will be the therapeutic gain?
Dr. Abbruzzese pointed out that taking a “business as usual” approach and just attacking a single target may not really be effective for a disease as complex and aggressive as pancreatic cancer. The current approach of focusing on a single target generally results in a magnitude of difference in survival of only a few weeks. “We really need to begin thinking about combinations of these targeted agents going forward, and we really have to find out how we can intervene earlier in pancreatic carcinogenesis,” he said.
Among the new targets Dr. Abbruzzese discussed is a family of nuclear transcription factors that control many different aspects of cell growth, the ability to metastasize and the ability to resist traditional chemotherapy and radiation. “We think that by targeting some of these transcription factors, in particular NF-kB, we may be able to make more of an impact than by targeting some of the other proteins further upstream.” On the subject of potential new treatments, Dr. Abbruzzese revealed that preclinical studies suggest that curcumin, a component of turmeric, inhibits activation of NF-kB. Data from these studies indicate that curcumin has growth inhibitory and proapoptotic effects against diverse tumors in vitro. In addition, curcumin has chemopreventive and antitumor effects in animal models. Phase I studies in humans showed that curcumin has virtually no toxicity, but bioavailability is an issue.
Dr. Abbruzzese concluded his presentation by suggesting that clinical investigators should
•Examine early events in pancreatic carcinogenesis to define targets for chemoprevention
•Develop risk models based on genetics and molecular epidemiology to identify “at risk” subjects for early detection and screening
•Stop conducting clinical trials that only seek incremental gains
•Develop techniques to rapidly interrogate cancer cells recovered from patients to individualize therapy
•Break down barriers to combine novel investigational agents. |
