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PURPOSE
The major focus of CORI’s research will be focused in gastrointestinal cancers (including colorectal, pancreas and liver), melanoma, breast cancer, and cancer related-imaging with the aim of developing new therapeutics.
Gastrointestinal Cancers (GI)
GI cancers are the second most common cause of cancer-related deaths in the United States. In 2007, there were 271,250 GI cancers in the United States with 134,710 deaths. Additionally, colon cancer was the fourth most common cancer in California with 15,000 cases, and was second only to lung cancer with more than 5,000 deaths. While surgery remains the most effective treatment, few patients will be cured by surgery alone, due to the severity of the disease at the time of diagnosis.
Survival has been impacted by inadequate methods of early detection and more effective systemic therapies. Improving these statistics will require further research into methods of early cancer detection and the development of innovative therapies. The lack of research funding in GI cancers has had a devastating effect on those afflicted with these diseases, with the ratio of deaths to new cases remaining approximately 1 to 1.
As compared with other cancers, especially breast and prostate, GI cancer deaths continue to be unacceptably high. According to the American Cancer Society (ACS), the incidence of colon cancer cases in California is the highest in the nation. Thus, the ACS also reports that the state of California has the largest number of colon cancer deaths. However, in recent years, some progress has been made in creating a greater public awareness of colon cancer through education programs on screening. This exposure has resulted in some increased funding for colon cancer research, and the future looks promising.
Melanoma
Melanoma, the most deadly form of skin cancer, is primarily related to excessive sun and ultraviolet light exposure. In the United States, the lifetime risk of developing melanoma has increased dramatically from 1 in 1,500 individuals in 1935 to a staggering 1 in 75 today. The statistics for Californians are even grimmer. According to the California Cancer Registry (CCR), the state’s population-based cancer surveillance system, there were 5,700 new cases of invasive melanoma in 2007 and more than 800 deaths, the highest statistics of any state in the nation. CCR reports that in California, the incidence of melanoma has increased by 15% in the last decade. The number of cases of melanoma increases dramatically with age, with half of all cases occurring in adults 50 years of age and older. With the median age of patients around 50, the years of lost productivity is greater than most cancers.
Even more disturbing is a recent University of Southern California study, which examined more than 700,000 cancer cases in Los Angeles County over a 25-year period. The study demonstrated that rates of most cancers are declining in the county, but rates for melanoma are increasing dramatically. The study revealed that melanoma case numbers have increased so quickly in the last 20 years that it is now one of the region’s five most common cancers, with similar alarmingly increasing incidences in all parts of the State.
Melanoma, when identified early, is curable by surgery alone, but once it has spread throughout the body (metastasized), the chance for survival is poor. Few patients with advanced melanoma are eligible for potentially curative surgery. Unfortunately, melanoma is also relatively resistant to chemotherapy or radiation. Biologic agents such as interferon and interleukin-2 have not significantly improved survival rates, and these agents are quite toxic.
These are the only two drugs that have been FDA-approved for the treatment of melanoma in the last 30 years, while numerous drugs have been developed both in the United States and abroad. With the incidence of melanoma increasing, and very few new drugs being approved, there is a clear need to develop further treatments.
Breast Cancer
In 2008, it is expected that 182,000 women in the United States will develop breast cancer, making it the leading cause of cancer morbidity second only to lung cancer in death rates. Similar to other solid tumors such as melanoma and GI malignancies, control of the initial disease is critical, as the presence of local or regional metastases can lead to disease progression and ultimately, patient death. While a variety of targeted therapies have been developed in recent years focused on treatment after the tumor has spread, the cure for breast cancer will come with improvements in understanding the mechanisms of disease initiation and metastases to the regional lymph nodes. Critical to working toward the cure, are improvements in early diagnosis through screening tests (imaging) and surveillance.
Although a number of methods can increase the detection of micrometastases, i.e., small metastases that are difficult to identify by standard examination, these techniques are usually too costly for routine evaluation of surgical specimens. Sentinel node biopsy (SNB), a selective surgical sampling technique to identify the first tumor-draining lymph node, has been widely accepted for its accuracy in melanoma and breast cancer. However, despite this test being incorporated into routine cancer care, the test is not always accurate, and the status of the sentinel node doesn’t always predict the outcome of the patients. New methods of evaluating the sentinel node or improved methods of analysis of the primary tumor could lead to improved methods of staging disease status and predicting patient outcome.
For all cancers, imaging is critical for diagnosis, staging and judging responses to therapy. Improvements in traditional imaging such as CT and MRI have made been made in recent years, yet the ability to accurately determine patient eligibility for surgery and/or chemotherapy remains imprecise and other methods to determine responses to therapy and comparison to the tumor biology are poor. The development of whole-body positron emission tomography (PET) imaging using radio-labeled glucose derivatives has improved imaging, but remains untested for judging tumor biology.
Stem cell research will likely provide the key to understanding the biologic evolution of malignancies, especially breast cancer. As part of this research effort, embryos in young women can be frozen prior to receiving chemotherapy and given back to these patients when treatment is completed in the event they wish to have children.
Oncoplasty describes reconstructive approaches after cancer treatment and in women after mastectomy. Understanding cellular mechanisms of wound healing and tissue regeneration is fundamental to achieve a better cosmetic result.
With a recent study demonstrating that psychological wellness reduces breast cancer recurrence by 50%, it is essential to work in a center that provides all the necessary components. These include psychological support, massage therapy, meditation, and acupuncture.
Gastrointestinal Cancers (GI) Program
The major focus of this program is to improve staging accuracy in gastrointestinal cancers and develop innovative, more effective therapeutic strategies. To this end, multicenter clinical trials have been initiated which will provide important outcome data and this can be correlated with basic science genomic studies performed in our laboratories.
International multicenter trial to improve staging accuracy in colon cancer
In October 2008, the National Cancer Institute (NCI) approved our international trial in colon cancer. This trial went through a very stringent peer review process and involves the United States Military Cancer Institute (USMCI), Israel and Serbia. The protocol was approved in December, 2008 and has been approved by the Institutional Review Boards (IRB) in both Israel and Serbia. The overall goal of this study is to develop improved methods for staging early colon cancer and to better select candidates for postoperative chemotherapy. For some patients this will translate into a better survival while in others the toxicity and expense of chemotherapy for those patients who may already be cured can be avoided. There is a lot of interest in this study because it is the only trial that combines quality surgery, pathology and genomics in colon cancer.
Genomic analysis and gene signatures in colon cancer
By working in conjunction with ten other institutions, this trial will enable us to pursue additional hypotheses within the context of a large patient population. As a corollary to this trial, we will examine molecular characteristics of tumors to create a prognostic index based on multiple biologic specimens. These studies will be performed with Dr. Dennis Slamon at the University of California, Los Angeles (UCLA) basic science laboratories. The ultimate goal of this study is to individualize patient care using the most sophisticated technology and science available.
Innovative therapeutic strategies in liver cancer
Another area of interest is pursuing our research in liver cancers. Many cancers spread to the liver and many patients succumb to liver failure. We have made significant strides in prolonging survival by developing novel surgical approaches and using these in combination with recently approved chemotherapeutic and biologic agents. At the same time we have studied mechanisms of metastases (cancer spreading) in our laboratory to identify pathways that may become targets for new therapies. This research has culminated in numerous peer-review publications.
Melanoma Cancer Program
The immune environment in Melanoma Sentinel Lymph Nodes
Cytokines are biochemical factors (peptides) produced by a variety of inflammatory cells and play a central role in the function of the immune system, controlling everything from allergic reactions to responses to bacterial and viral infections and cancer. We have conducted studies that suggest that one way in which melanoma spreads from the skin is by stimulating the adjacent regional lymph nodes to make a cytokine called interleukin-10 (IL-10). IL-10 interferes with the normal patient’s immune response to cancer. In fact, higher levels of IL-10 (genes “turned on”) in the blood of melanoma patients is directly associated with poor patient survival (higher death rate).
We will work to understand in greater detail the process by which melanoma escapes attack by the immune system, and how cytokines, such as IL-10, function in the spread of melanoma in the lymph nodes. We also will work to develop methods to halt the production of IL-10 and other immune suppressive agents as a novel approach for immune or vaccine therapy. These experiments should lead to improved methods of boosting the patient’s own immune defenses to stop the spread of cancer. By producing a patient profile that defines exactly which cytokines are operating in the cancer-containing lymph nodes, we hope to be able to develop cytokine-mediated therapies that can produce a cure. Also, by defining the cytokine “milieu” within nodes, we may be able to develop more accurate prognostic markers which can be used to test and monitor patients disease.
Immune reactivity and patient genetics
Our previous research studies have demonstrated that not only are the lymph nodes located closest to the primary melanoma as being immunosuppressed but perhaps as the cancer grows a more global systemic immunosuppression occurs. A number of inflammatory genes have been shown to be altered in cancer patients and may contribute to the inability of patients to pose a viable immune response. We have found one such inflammatory gene that appears to be inactive in melanoma.
Chemokine receptor 5 mutations have been identified in about 15% of melanoma patients with advanced disease and patients with these mutations all die of melanoma; while patients who do not have this mutation appear to have a much better survival. This research is extremely promising and needs to be expanded with our current projects. We suspect that part of the immune dysfunction found in melanoma may relate to the patient’s genetically determined immune properties. We plan to evaluate the individual gene expression patterns of our patients and how they relate to the immune response to melanoma.
Our goal is to relate immune function to patient outcome. Due to a considerable acceleration of the technologies available for cellular analyses made possible by recent breakthroughs in genomic sciences, we now possess advanced biochemical techniques that can identify the cytokine profile and genes (“milieu”) in these tumor samples. Our goal here is to apply the newest techniques to our historic (“archival”) tissue and blood samples, to identify the different cytokine profiles and gene expressions that correlate with outcomes of individual patients.
The results from these experiments are critical for understanding how the immune system functions in melanoma and for the development of more effective therapies for this disease.
Functional aspects of primary melanoma tumors
We have collected a series of primary melanoma tumors that has allowed us to evaluate gene expression from this tissue. While this technology has been successful in larger cancers such as breast and colon cancers, the task to collect melanoma tumors is much more difficult based on the small size of the skin tumors. We have used cDNA microarray technology to identify several genes, including VEGF and LIMK that may serve as predictive of patient outcome. Over-expression of these genes in the primary tumor is predictive of spread of the melanoma to the adjacent lymph nodes. We anticipate further expansion of these studies to evaluate the gene expression in additional melanoma primary tumors as a method to predict spread of disease to the regional lymph nodes and distant sites. These concepts are novel and are covered as a unique finding patented by us through the United States Patent office.
New Ideas for Sunscreen for Melanoma
Melanoma and non-melanoma skin cancers are predominately caused by excessive sunlight exposure and damage to the skin. UV light exposure damages normal genes and leads to instability, cellular atypia and ultimately skin cancer. Current sunscreens provide a physical block to UV radiation but provide no protection to the skin once the damage has occurred. By identifying the abnormally expressed genes in the primary tumors (section 3), we can develop a new approach to developing sunscreens. We propose methods of blocking expression of the abnormal genes in these skin cells by topical application of agents delivered to the skin in people with a high risk of developing skin cancer including melanoma. These lotions could be used alone or combined with conventional sunscreen. The concept of creating a topically applied agent for prevention of skin cancer was patented by us through the United States Patent office and has extension of the patent in Europe and Australia.
Breast Cancer Research Program
In the last ten years, there have been significant advances in the treatment of breast cancer with improvements in surgery, i.e. sentinel node technology, drug therapy, i.e. Herceptin, and molecular biology with methods to identify the genetic signatures of these cancers to provide individual patient prognosis. While these advances have changed the way we stage and treat breast cancer, many patients still suffer significant morbidity and more than 30% still die from the disease.
Evaluating the Immune Environment in Breast Cancer Sentinel Lymph Nodes
While sentinel lymph node technology allows surgeons a minimally invasive method to stage the regional lymph nodes, there is little data available about the immune interactions of breast tumors and the adjacent axillary lymph nodes. Most of the emphasis of evaluating the immune response in cancer has focused on cancers such as melanoma. We propose the same principles of physical interactions of the primary tumors and regional lymph nodes seen in melanoma are applicable in breast cancer. Preliminary data from breast cancer sentinel nodes suggests that these lymph nodes are immunosuppressed similar to those found in melanoma.
We will work to understand in greater detail the process by which breast cancer escapes attack by the immune system, and how cytokines, such as IL-10, function in the spread of breast cancer to the lymph nodes. We also will work to develop methods to halt the production of immune suppressive agents as a novel approach for immune therapy for the regional lymph nodes. These experiments may lead to improved methods of boosting the patient’s own immune defenses to stop the spread of breast cancer. By producing a patient cytokine profile from the regional lymph nodes we may better define the exact cytokines are that are operative in the cancer-containing and normal lymph nodes. Also, by defining the cytokine milieu within nodes, we may be able to develop more accurate prognostic markers which can be used to test and monitor patients disease.
PET imaging for breast cancer
Whole-body positron emission tomography (PET) imaging was developed as a method to identify cancer in patients based on the relatively high uptake of the imaging agent, FDG, in tumors compared to normal tissues. In recent years PET imaging has become part of the imaging used in detecting metastatic breast cancer and now smaller imaging devices appear to have a role in detecting breast tumors not identified by other test. We have focused research on the development of a hand-held PET-sensitive probe that may help surgeons to localize breast tumors, establish the margins for tumor removal and detect the presence or absence of cancer in the regional lymph nodes. These studies will be performed to evaluate the genetic profiles of the tumors and compare to the relative uptake of FDG in the cancers. The concept is that the genetic profile of the tumors may be seen by PET imaging and the expected response to therapy could be predicted by uptake of FDG evaluated by conventional PET imaging or by use of a hand-held FDG sensitive probe used in the operating room.
In the last ten years there have been significant advances in the treatment of breast cancer with improvements in surgery, i.e. sentinel node technology, drug therapy, i.e. Herceptin, and molecular biology with methods to identify the genetic signatures of these cancers to provide individual patient prognosis. While these advances have changed the way we stage and treat breast cancer, many patients still suffer significant morbidity and more than 30% still die from the disease.
Evaluating the Immune Environment in Breast Cancer Sentinel Lymph Nodes
While sentinel lymph node technology allows surgeons a minimally invasive method to stage the regional lymph nodes, there is little data available about the immune interactions of breast tumors and the adjacent axillary lymph nodes. Most of the emphasis of evaluating the immune response in cancer has focused on cancers such as melanoma. We propose the same principles of physical interactions of the primary tumors and regional lymph nodes seen in melanoma are applicable in breast cancer. Preliminary data from breast cancer sentinel nodes suggests that these lymph nodes are immunosuppressed similar to those found in melanoma.
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