Research Highlights
Combining the use of state-of-the-art computers, cutting-edge engineering and high-energy rays to pinpoint and destroy cancer cells, program researchers are working across the bench-to-bedside continuum to harness the power of radiation for the benefit of patients worldwide. Here is a summary of their recent accomplishments:
- An ongoing multicenter Phase III trial of the hypoxic cell cytotoxin TPZ, discovered by Dr. Martin Brown at Stanford, combined with cisplatin and fractionated radiotherapy for Head and Neck Cancer is being tested at Stanford by Drs. Le and Pinto in HNSCC. During the last 7 years, 10 patients a year have been put on this trial.
- The ability of the recombinant cytosine deaminase-expressing C. sporogenes to produce sufficient conversion of 5-FC to 5-FU was tested in vivo with antitumor activity as an endpoint. The combination of 5-FC plus recombinant spores produced a similar or even greater growth delay than that produced by a maximum tolerated dose of 5-FU given on the same schedule ( Gene Therapy 9:291, 2002 ). These data establish the efficacy of tumor-specific targeting of an anticancer drug delivery system using this obligate anaerobe and is awaiting FDA approval for a phase I clinical trial at Stanford lead by Drs. Le and Brown.
- Identification of small molecule that are preferentially cytotoxic to cells that lack VHL tumor suppressor gene is being performed by Drs Giaccia and Brown. These small molecules represent a new class of targeted compounds for renal cell cancer ( Nat Rev Drug Discov 2:803, 2003 ).
- The SELDI-TOF MS technique was used by Dr. Le, Giaccia, and Koong to identify new hypoxia secreted proteins ( J Clin Oncol 2005 ). The protein galectin was identified as a hypoxia-secreted protein that provides a link between tumor hypoxia and immune privilege. Tissue sections from 101 head and neck cancer patients were used to confirm the experimental results. Studies are being developed to determine if inhibiting galectin will increase the cellular immune response against hypoxic tumor cells.
- HIF-1 a family members are highly unique proteins in that they exhibit a very unique sensitivity to oxygen and oncogenic mutations that has been investigated by Dr. Giaccia ( J Biol Chem 277:40112, 2002, Cell 118:781, 2004, Genes & Development 18:2183, 2004, Mol Cell 17:503, 2005 ). He and Drs Denko and Brown are exploiting the finding that HIF-1 controls oxygen consumption and inhibition of HIF-1 increases cell killing by hypoxic cell cytotoxins. This finding provides the scientific rationale to combine HIF inhibitors with hypoxic cell cytotoxins.
- Thromboembolic disorders and metastatic disease are often found together in cancer patients. Drs. Denko, Giaccia and Le proposed that the physiology of the solid tumor leads to the existence of chronic hypoxia, and it is the hypoxic up-regulation of genes that regulate blood clotting that drives these processes ( Cancer Res 61:795, 2001; Oncogene 22:5907, 2003; Cancer Metastases rev 23:293, 2004 ). Thus, strategies that attempt to oxygenate a tumor should be beneficial to anticancer therapies such as radiotherapy or chemotherapy as investigated by Dr. Dan Kapp (IJROBP 54:58, 2002) and should also decrease metastatic spread of tumor cells induced by a low oxygen environment.
- A Phase I dose escalation study was performed to determine the safety of radiosurgery to treat pancreatic cancer with 15 locally advanced pancreatic cancer patients by Drs. Koong, Le, Fisher, Ford and Gibbs ( IJROBP 58:1017, 2004 ). They found that a single dose of 25 Gy was able to achieve local control without the appearance of grade 3 or higher gastrointestinal toxicity.
- A Phase II study was performed to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer (IJROBP 63:320, 2005). In this study 19 patients had pathologically confirmed adenocarcinoma of the pancreas. These patients 45 Gy concurrent with 5-FU that was followed by a 25 Gy stereotactic boost. 15 of the 16 patients that finished therapy were free from local progression until death with medial survival being 33 weeks. This protocol results in excellent local control, but does not increase overall survival due to metastatic disease. New Phase II studies are planned using 25 Gy stereotactic radiosurgery alone with different chemotherapy and targeted therapy combinations to control disseminated disease.
- Spatially resolved metabolite maps, as measured by magnetic resonance spectroscopic imaging (MRSI) methods, are being increasingly used to acquire metabolic information to guide therapy, with metabolite ratio maps perhaps providing the most diagnostic information. Dr Xing and colleagues developed a quality assurance procedure for MRSI-derived metabolic data that can be used for guiding conformal radiotherapy ( IJROB 57:1159, 2003 ). They recently developed and published a narrow band deformable image registration algorithm for direct registration of ER-based prostate MRI/MRSI and CT studies ( IJROB 62:595, 2005 ). Both hypothetical tests and patient studies have indicated that the registration is reliable and provides a valuable tool to integrate the ER-based MRI/MRSI information to guide prostate radiation therapy treatment.
- Preoperative prostate-specific antigen velocity (PSAV), or the rate of PSA rise before diagnosis, predicts for risk of cancer death after radical prostatectomy. Dr. King, Presti and Brooks evaluated the relative merit of established preoperative factors, including biopsy indices and preoperative PSAV, for their impact on relapse after radical prostatectomy for 202 patients with prostate cancer. They reported ( JCO 23:6157, 2005 ) that the preoperative PSAV is a significant independent clinical factor predicting for relapse after radical prostatectomy and also predicts for larger, more aggressive, and more locally advanced tumors. Its inclusion should be useful in risk stratification, evaluation for alternatives to surgery, and patient selection for neoadjuvant or adjuvant therapies as part of randomized clinical trials.
- The advent of specific molecular markers and probes employing optical reporters has encouraged the application of in vivo diffuse tomographic imaging at greater spatial resolutions and hence data-set volumes. Dr. Graves applied singular-value analysis (SVA) of the fluorescence tomographic problem to determine optimal source and detector distributions that result in data sets that are balanced between information content and size. His data provide guidelines for the design of small-animal diffuse optical tomographic imaging systems and demonstrate the utility of SVA as a simple and efficient means of optimizing experimental parameters in problems for which a forward model of the data collection process is available ( J Opt Soc Am A Opt Image Sci Vis 21:231, 2004 ).
- With the current spatial resolution of intensity modulation, it is often inevitable to irradiate more sensitive structures or to sacrifice the tumor dose coverage to protect the adjacent sensitive structures. An integrated system of high spatial resolution IMRT to utilize maximally the technical capacity of the IMRT technology is being developed at Stanford by Dr. Xing, Graves and colleagues. This high spatial resolution IMRT will provide substantially improved dose distribution that would otherwise be impossible. The improvement will lead to a greater local control of cancer and less normal tissue complications.
- Gene expression profiling following exposure of wild-type yeast to TPZ, ionizing radiation, UV radiation, cisplatin and hydrogen peroxide was performed in collaboration between Dr. Ron Davis and Dr. Martin Brown. Genes that were induced by these stresses were compared to those genes which when deleted produce sensitivity to these agents. There is no relationship between the genes whose expression is increased (or decreased) and those that provide resistance to the agents. These data have important implications for the relevance of damage induced genes in promoting cell survival ( Proc Natl Acad Sci USA 98:12608, 2001, Proc Natl Acad Sci USA 99:8778, 2002 ).
- Drs. Le, Denko, Pinto, Koong Tibshirani, and Giaccia identified new biomarkers for tumor hypoxia using a combination of genomic and proteomic analyses. Plasma osteopontin (OPN) was the first and the most robust biomarker that correlated with tumor pO 2 in 54 HNSCC patients ( Clin Cancer Res 9:59 , 2003 ). Two other groups have also independently reported that OPN correlates with tumor hypoxia and patient survival. Therefore, OPN appears to be a significant prognostic marker for tumor relapse and survival in HNSCC patients with hypoxic tumors.
- The presence of a complete (BH1-3) apoptotic molecule is necessary for the induction of the intrinsic apoptotic cascade. However, it is unclear what are roles of the many BH3 only pro-apoptotic molecules. Based on toxicity in yeast, three functional categories of BH-3-only pro-apoptotic proteins can be classified: those that kill directly such as tBid, those that sensitize that work in a Bcl-2 dependent manner such as Bad, and those that are non-toxic such as Bnip3 and Bnip3L ( FASEB 19:464, 2005 ).
- Perp is a direct p53 target discovered by Dr. Attardi, and its overexpression is sufficient to induce cell death in fibroblasts, implicating it as an important component of p53 apoptotic function. Through the generation of Perp-deficient mice ( Cell 120:843, 2005 ), the role of Perp in the p53 apoptosis pathway in multiple primary cell types was determined by comparing the cell death responses of Perp null cells to those of wild-type and p53 null cells. These experiments demonstrate the involvement of Perp in p53-mediated cell death in thymocytes and neurons but not in E1A-expressing MEFs, indicating a cell type-specific role for Perp in the p53 cell death pathway. In addition, we show that Perp is not required for proliferation-associated functions of p53. Thus, Perp selectively mediates the p53 apoptotic response, and the requirement for Perp is dictated by cellular context.
- Generation of new mouse models to study p53 activity in response to stress in vivo . Conditional knock-in mice have been generated by Dr. Attardi and in collaboration with Dr. Giaccia have proved useful in dissecting the importance of transactivation in p53 stress responses such as ionizing radiation, chemotherapy and hypoxia ( Nat Genetics 37:145, 2005 ).
- The SELDI-TOF MS technique was used to generate multiple proteomic spectra from plasma samples of patients with HNSCC and those without known neoplastic disease. A new bioinformatics method known as the "Lasso" algorithm was developed by Dr. Robert Tibshirani to extrapolate proteomic patterns that can best discriminate HNSCC patients from non-cancer controls in a training set of 109 subjects ( Clin Cancer Res 10:4806, 2004 ). The "Lasso" technique was then applied to a separate masked test set of 107 patients. This approach can be used to separate HNSCC patients from non-cancer controls with moderate sensitivity and specificity.
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