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 of 2008 and has been submitted to the Institutional Review Boards (IRB) in 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 in our 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.