At UC Santa Cruz, cancer genomics research is yielding new understanding about cancer's inner workings. Cancer genomics tools developed at UC Santa Cruz, including the UCSC Cancer Genomics Browser, provide a complete analysis pipeline from raw DNA reads through the detection and interpretation of mutations and altered gene expression in tumor samples. UCSC biomolecular engineers Joshua Stuart, Nader Pourmand, and David Haussler from the UC Santa Cruz Genomics Institute bring this genomics expertise to collaborations with clinical researchers at medical centers nationally, including members of the Stand Up To Cancer “Dream Teams” and the Cancer Genome Atlas (TCGA), to discover molecular causes of cancer and pioneer a new personalized, genomics-based approach to cancer treatment. UCSC contributes to clinical teams by developing new technology in clinically oriented cancer genomics, including genomic data and electronic medical records.
UCSC Informatics–UCSF Clinical Collaborations
The UC Santa Cruz cancer genomics group, part of the UC Santa Cruz Genomics Institute, teams up with QB3 clinical investigators from UC San Francisco to offer expertise that deepens the value of cancer clinical trials. One such project will result in a centralized pancreatic cancer genome browser (PCGB) that hosts and organizes curated genomic data and offers data visualization and analysis.
The INSTINCT project, a QB3-based multidisciplinary collaboration between UC Santa Cruz and UC San Francisco, applies genomic knowledge to clinical research to address important scientific and health problems in the areas of cancer, autoimmune diseases, and neurological diseases.
Another collaboration between UC Santa Cruz and clinicians at UC San Francisco focuses on the I-SPY 2 breast cancer clinical trial, the first cancer clinical trial to apply whole-genome sequencing across all patients and multiple time points in a trial. A national study, I-SPY 2 aims to identify biomarkers predictive of response to therapy throughout the treatment cycle for women with locally advanced breast cancer. The hope is to gain a deeper understanding of the genetic mutations that give rise to breast cancer and are involved in therapeutic response or resistance.
Big Cancer Data
The UCSC Cancer Genomics Hub (CGHub), a product of the Haussler lab, is a secure repository for storing, cataloging, and accessing cancer genome sequences, alignments, and mutation information from TCGA, a pioneering project involving more than 20 cancer types, the TARGET project, which focuses on the five most severe childhood cancers, and other related projects. The current planned capacity of this data center is five petabytes. We anticipate that the CGHub and will serve as a platform to aggregate other large-scale cancer genomics information, growing to provide the statistical power to attack the complexity of cancer.
Social Networking for Cancer
Ted Goldstein, an alumnus of both the Haussler and Stuart labs (currently a CBSE associate) is developing a novel cloud-based software application—MedBook—that creates a rapid learning community where scientists, clinicians, and patients collaborate through social media to deliver individualized treatments and better outcomes for cancer patients. This “app” platform matches patients to treatments and clinical trials based on electronic medical record data and the molecular subtypes of their tumors. It learns as it goes, capturing and transforming genomic and outcomes data into new knowledge. Each patient receives treatment based on the best available knowledge from the collective community.
Anti-Cancer Drug Discovery
Biochemist Scott Lokey directs the UCSC Chemical Screening Center (CSC), dedicated to improving human health by finding the next generation of therapeutic agents against a wide variety of diseases, including cancer. The CSC is driving innovation in drug discovery by bringing together experts in drug screening with cell and molecular biologists engaged in disease research. Modern “-omics” technologies such as shRNA, expression profiling, deep sequencing, and proteomics have delivered vast data sets that biologists are beginning to mine for clues into the molecular basis of disease. As a result of these efforts, a wave of new candidate drug targets has emerged.
Biochemist Roger Linington identifies and isolates bioactive natural products extracted from marine bacteria collected from the West Coast. His group is in the process of determining the structures of three possible new anti-cancer drugs and wiill develop a strategy to produce these materials in bulk for further evaluation.
Biochemist Glenn Millhauser is studying a novel class of signaling proteins for improving cancer therapies, designing proteins and collaborating with medical school researchers to create injectable drugs for treating melanoma and cancer cachexia.
Microbiologist and environmental toxicologist Manel Camps studies the biological consequences of random changes in genetic mutations that occur spontaneously or as a result of environmental insults. They use induction of random genetic alterations (mutagenesis) as an indicator of DNA damage for high-throughput analysis of chemical libraries. Through this approach, Camps and his colleagues exploit the particular susceptibility of rapidly replicating cells to DNA damage for therapeutic purposes, with the long-term goal of identifying candidates that complement or enhance existing anti-tumor therapies.
Molecular, cell, and developmental biologist Bill Sullivan focuses on the structural and regulatory mechanisms that drive cell division. One aspect of this is testing candidate drugs for their effects on cell division.
Cancer Stem Cells
Biomolecular engineer Camilla Forsberg focuses on stem cell fate decisions of the blood system. Hematopoietic stem cells are responsible for generating a life-long supply of all the types of mature blood cells. She investigates what factors dysregulate the blood developement system to cause cancer and other disorders. Unverstanding the molecular determinants of hematopoietic stem cell fate decisions can lead to prevention and treatments for genetic and acquired disorders of the blood system, including leukemias and lymphomas.
Rapid DNA Sequencing
Biomolecular engineer Mark Akeson and biochemist David Deamer are developing new technology for rapid DNA strand sequencing by using protein nanopores—technology that will enable cancer genome sequencing.
Lab on a Chip
Electrical engineer Holger Schmidt is developing a lab-on-a-chip device for detecting cell-free nucleic acids found at elevated levels in the bodily fluids of individuals with cancer. The device combines microfluidics with a sensitive fluorescence excitation and detection platform that relies on liquid-core waveguides. Testing of the integrated device will focus on detecting nucleic acids associated with high-risk human papilloma virus, followed by testing in melanoma patients, a healthy human, and a leukemia patient. If successful, the project will enable a transformative step for cancer diagnosis: non-invasive, quantitative analysis of biomarker panels from cell-free DNA.
Molecular, cell, and developmental biologist Lindsay Hinck investigates how epithelial cells assemble into organs during development and how the reverse process occurs during cancer, when cells disassemble and metastasize to inappropriate locations. Her lab focuses on how cells' positional cues control mammary gland development and how loss of these cues during tumor progression contributes to breast cancer. Only about 15% of breast cancers have been linked to specific gene mutations; therefore, a major challenge in breast cancer research is to identify the causes of the disease. The Hinck lab has identified breast tumor suppressors that regulate several critical pathways controlling cell proliferation and migration. Their current research focuses on developing therapeutic strategies to target these pathways.
Molecular, cell, and developmental biologist Martha Zúñiga investigates regulatory mechanisms during immune responses to skin transplants, which are epithelial cell-derived exosomes. These have potential implications in cervical cancer because human papilloma viruses infect epithelial cells. She collaborates with the Haussler lab to use genomic, immunological, and cell biology tools to identify genetic sequences that predispose to, or conversely, protect from inflammatory autoimmune diseases such as ankylosing spondylitis. She collaborates with dermatologists to establish a system to study the role of ionizing radiation in predisposition of human skin to melanoma. This project examines the effect of ionizing radiation on the integrity of the cutaneous immune system and on the expression of genes implicated in early molecular events leading to the development of melanoma.
Biomolecular engineer David Haussler and research biologist Sofie Salama explore the molecular events that lead to gliomas, a form of brain cancer. They work with a network of collaborators to reveal common mutations and genomic rearrangements associated with gliomas. These genomic features enable identification of patients whose cancer is likely to progress quickly and require the most aggressive treatment versus those who can benefit from a more conservative approach. In parallel their laboratory generates induced pluripotent stem cells (iPSCs) that have genetic lesions common to lower-grade gliomas. These genetically modified iPSCs can be differentiated to neural progenitors—a model of glioma cancer stem cells—to characterize their growth and differentiation properties and test their responsiveness to cancer drugs.
More Cancer Research at UC Santa Cruz
Biochemist Seth Rubin explores how tumor suppressors work, pursuing an innovative approach to blocking cancer cell division through chemically rescuing the anti-proliferative activity of the retinoblastoma tumor suppressor protein.
Molecular, cell, and developmental biologist Jeremy Sanford studies the genetic changes that cause pancreatic cancer. He is working to change the fate of pancreatic cancer cells, performing experiments in animal models to evaluate the significance of specific IGF2BP3-regulated genes in tumor formation.
Biomolecular engineer Phillip Berman applies knowledge of abnormal gene expression in colorectal cancer to develop a vaccine against cancer cells.
Molecular, cell, and developmental biologist Doug Kellogg investigates how cell growth, size, and division are regulated in normal cells and what goes wrong in cancer.
Microbiologist Karen Ottemann investigates how H. pylori causes gastric cancer.
Biochemist Michael Stone studies the mechanisms for telomerase activation, a process tightly regulated in rapidly dividing cell types such as stem cells and tumors.
Biochemist Carrie Partch studies how molecular clocks control cancer cell division.