Researchers in the lab are focused on identifying lesions associated with the tumorigenesis and metastasis. The Surgical Oncology Tumor Bank has been invaluable in advancing this research possible. For example, the lab was able to help validate the role of microRNAs in a mouse model of pancreatic neuroendocrine tumors using human neuroendocrine tumor specimens. The lab is also investigating the role of Sall2 in conferring resistance to cancer therapies, how TNFR1 signaling contributes to the inflammatory response and cell apoptosis, and the role of colon cancer stem cells in perpetuating tumor growth.
Exploring the Relationship between Sall2 and Cancer Growth
Drs. Pincheira, Donner, and Warren have identified a novel factor called Sall2 that binds cell surface receptors for nerve growth factor. Sall2 appears to act at the cell surface to coordinate the activities of the nerve growth factor receptors and within the nucleus of the cell to regulate gene expression. The genes affected by Sall2 play an important role in regulating the development of neurons, most particularly in the development and extension of neurites from developing neurons. Thus, collaborative efforts with members of the Department of Neurology are underway to understand the mechanisms through which Sall2 plays a positive regulatory role in the development of the nervous system, and possibly in neurodegenerative pathologies.
As mechanisms that regulate neurite extension are similar to those used by cancer cells to spread, to metastasize, Drs. Pincheira, Donner and Warren investigated whether Sall2 might play a role in the initiation, growth, or spread of human colon cancer. Remarkably, strong evidence suggests that Sall2 may play a role promoting the resistance of cancer cells to chemo- and radiation therapies and may predict whether colon cancer is likely to recur after surgery.
We have found that Sall2 activates genes that encode survival proteins, thus rendering cancers particularly resistant to therapies. This observation suggests that cancers may be rendered sensitive to efforts to kill them by suppressing Sall2 expression. Efforts in this direction are ongoing.
We have also found that expression of variant forms of Sall2 in human metastatic colon cancer samples recovered from our surgeries increases the likelihood the cancer will recur. This observation has led members of the Surgical Oncology Research Laboratory to initiate studies of how these Sall2 variants, called single nucleotide polymorphisms or SNPs, may function within the complex environment of human cancer.
Deranged Function of Tumor Suppressor Proteins
Tumor suppressor proteins are the brakes that impede the deregulated and inappropriate cell growth found in cancer. Under the leadership of Dr. Warren, members of the Surgical Oncology Research Laboratory have been scanning the genome of human metastatic colon cancer samples, and other malignancies as well, in order to identify lesions arising from mutated or inappropriately expressed tumor suppressors.
A particularly interesting tumor suppressor is Mig-6, which inhibits signaling events induced by activated receptor protein tyrosine kinases. In a study of papillary thyroid cancer, Dr. Warren and his colleagues found that high expression of Mig-6 was associated with longer survival and favorable outcomes, thus showing that Mig-6 acts as a tumor suppressor protein in thyroid cancers.
Investigation of Mig-6 was extended to specimens of human metastatic colon cancer. Surprisingly, in this malignancy high expression of Mig-6 was associated with poor outcome. Two explanations for this result are under investigation: firstly, evaluation of the Mig-6 gene in colon cancer samples has led to the detection of mutant, and possibly non-functional, forms of the gene; and secondly, the expression of Mig-6 is driven by oncogenic events that may be operative within tumors. Thus, elevated Mig-6 expression may be reflective of a particularly aggressive tumor microenvironment. This latter possibility suggests that Mig-6 may function as a sentinel or biomarker that can identify colon cancers predisposed to rapid growth and/or spread.
Identifying biomarkers that can predict whether cancers are likely to recur or assume an aggressive phenotype is one of the goals of the Surgical Oncology Research Laboratory. With such biomarkers in hand we aim to individualize and personalize the treatments we offer to every patient.
Surgical Oncology Tumor Bank
The Surgical Oncology Tumor Bank contains tissue samples from more than 500 individual tumors that the lab has examined and catalogued, as well as a database of related information. By analyzing the growing body of data, we hope to identify a manageable number of subgroups - perhaps 10 or fewer - that will teach us how to predict cancer progression, and which treatments are most effective for each subgroup. We may find that some of these genetic subgroups of tumors are related, allowing us to map a "family tree" of cancer subtypes and identify which treatments are most effective for each branch of that tree.
Development of Targeted Therapuetics
The Surgical Oncology tissue bank is a repository for patient tumor specimens and matched normal tissue accumulated by UCSF surgeon-scientists Robert Warren and Eric Nakakura These specimens can be matched to clinical outcomes and the genes encoding important tumor suppressors and oncogens proteins been sequenced in each specimen, making them an invaluable research tool.
We have been able to grow these well-characterized tumor specimens in mice. The tumors retain the properties of the human malignancy, thus permitting us to test novel, targeted therapeutics against cancers with well-characterized genetic abnormalities. In pursuit of this goal, we are collaborating with Dr. Kevan Shokat, a UCSF researcher who has developed a novel panel of highly targeted small molecule drugs. These drugs inhibit cell surface receptor tyrosine kinases, mTOR, and additionally impair the capacity of mTOR to activate autoregulatory feedback mechanisms that impair the efficacy of drugs presently being used or tested for use in patients.
The significance of what has been enumerated above cannot be overstated. To obtain approval for and then to test new drugs in human patient populations can take decades. By using mice bearing human tumor specimens as surrogates we hope to rapidly evaluate and hopefully translate novel, targeted drugs to the clinic on behalf of or patents.
Molecular Biology of Neuroendocrine Tumors
Neuroendocrine (NE), or carcinoid, tumors of the GI tract frequently metastasize. Surgery is often not possible for patients with advanced disease, and current therapies are ineffective for shrinking tumors and durable palliation of debilitating symptoms. Our lab and others have made significant advances in the understanding of the biology of NE tumors:
Isolation of Colon Cancer Stem Cells
By implanting human tumors into mice, UCSF researchers have also isolated what we believe are colon cancer stem cells. These are cells which have properties similar to adult human stem cells, such as the capacity for self-renewal and the ability to differentiate into various types of specialized cells.
One hypothesis is that cancer stem cells are resistant to traditional chemotherapy treatment; over time, a recurrent tumor may derive from these cancer stem cells. By working to understand the molecular biology of this tiny subset of tumors cells, rather than the bulk tumor cells that have been analyzed in the past, the lab may find ways to overcome drug resistance and tailor treatments to hone in on any vulnerabilities. This may lead to long-term responses and perhaps even cures for some patients.
Life and Death Decision Making in Cancer Cells
Signaling through receptors that contain cytoplasmic death domains can induce cancers to regress or in some instances may paradoxically promote the growth and spread of malignancies. The decision-making that underlies whether cancer cells can be induced to self-destruct in response to cytokines such as tumor necrosis factor has been studied, and yet not well understood, for decades. The Surgical Oncology Research Team has shown that the type 1 TNF receptor (TNFR1), a prototype for understanding how cytokines act in cells, acts not only through its death domain but also through a signaling complex that contains non-receptor protein tyrosine kinases. Activation of this novel complex activates of PI 3-kinase/Akt/mTOR signaling and transcription factors, including NF-kB, that promote inflammation and cell survival.
The identification of this novel TNFR1 signaling complex goes some considerable way towards explaining why the response of cancers to immune-based therapies is so complex. Ongoing research is now being directed towards understanding how the TNFR1/tyrosine kinase-signaling complex engages and activates transcription factors that render cancers unresponsive to tumor necrosis factor. Achieving this goal may make it possible to more effectively activate immune responses through which the body may more effectively fight and clear cancers.