Zugl.: Tübingen, Univ., Diss., 2008

Indiana University-Purdue University Indianapolis (IUPUI) / Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers and is the leading cause of cancer death in the Unites States. Better treatments must be devised in order to improve the prognosis of this disease. Verteporfin, an FDA approved drug, has recently been reported to downregulate a potential core pathway of NSCLC, the Hippo pathway. The pathway consists of a kinase cascade to control the transcriptional coactivators YAP and TAZ. When these transcriptional coactivators lack phosphorylation of key residues, they are able to translocate into the nucleus and bind to the TEAD member of transcription factors. This augments transcription for genes responsible for proliferation, survival, and stem maintenance. In this study, we report that verteporfin limits proliferation and survival of NSCLC and may potentially be a viable treatment option. Inhibition of cell survival dose-dependently correlated with inhibition of YAP-TEAD transcription target CTGF. We also report the covalent homo-oligomerization of p62, a prominent protein involved with autophagy, with the introduction of verteporfin into NSCLC cells.

Kurz- und Langzeitergebnisse der Photodynamischen Therapie mit Verteporfinbei altersbedingter Makuladegeneration. / Short- and longtime results after photodynamic therapie with verteporfin, of patients with age-related macular degeneration.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Atypical teratoid rhabdoid tumor (ATRT) is a highly malignant pediatric central nervous system tumor. The prognosis is often poor, with a 2‐year survival rate estimated at 15%. This dismal prognosis highlights the need to develop new treatment modalities for this devastating pediatric tumor. Recently, a tumor suppressing signaling pathway known as Hippo has emerged as a possible cancer treatment target. The Hippo signaling pathway is involved in organ growth and maintenance, and is dysregulated in many diverse cancers. We used quantitative real‐time PCR to evaluate the mRNA expression profile of Hippo pathway genes. We then used determined the protein expression of various Hippo components using Western blots. The results of this study suggest that Hippo plays a definite role in atypical teratoid rhabdoid tumor.

Pancreatic cancer kills over 1700 people each year in Australia. In 2000, there were 1908 new cases diagnosed and it remains one of the least treatable malignancies. In the USA, it was the fourth leading cause of cancer death in 2004, with 31,860 new cases and 31,270 recorded deaths. Photodynamic therapy (PDT) is a novel, potentially useful treatment for locally advanced pancreatic cancer with only limited research and clinical work addressing this until now. PDT induces non-thermal, cytotoxic and ischaemic injury to a targeted volume of tissue. During PDT, a photosensitizer is activated by non-thermal light in the presence of oxygen, generating cytotoxic oxygen species and inducing cellular injury and microvascular occlusion. The aim of this thesis was to conduct an animal safety study using two second generation photosensitizers, talaporfin sodium and verteporfin, to assess the risks of pancreatic PDT by looking at injury to organs adjacent to the pancreas and assessing recovery from PDT treatment of the pancreas. The Syrian Golden hamster animal model was used to compare the results of this research to previous work by other authors. The study design incorporated a number of additional experiments, including quantitative tissue fluorescence techniques, plasma level analysis and histopathology techniques. The methods for the animal safety study were similar to the approach used in the clinical setting and provided vital data on the likely risks and side effects of phototherapy in humans. The first study, looking at talaporfin sodium, found likely risks of duodenal injury, gastric injury and death with a limited effect on normal pancreas at photosensitizer doses likely to be employed for pancreatic cancer PDT. The second study, using verteporfin, found similar results with a more potent effect on the normal pancreas at studied drug doses. Both agents had short drug-light intervals, ranging from 15 minutes to 2 hours, reducing the need for pre-treatment hospitalization and short photosensitivity periods of about one to two weeks. Some animals suffered minor cutaneous photosensitivity injuries. A human pancreatic cancer PDT pilot study is feasible and the risks and complications should be acceptable.

Pancreatic cancer kills over 1700 people each year in Australia. In 2000, there were 1908 new cases diagnosed and it remains one of the least treatable malignancies. In the USA, it was the fourth leading cause of cancer death in 2004, with 31,860 new cases and 31,270 recorded deaths. Photodynamic therapy (PDT) is a novel, potentially useful treatment for locally advanced pancreatic cancer with only limited research and clinical work addressing this until now. PDT induces non-thermal, cytotoxic and ischaemic injury to a targeted volume of tissue. During PDT, a photosensitizer is activated by non-thermal light in the presence of oxygen, generating cytotoxic oxygen species and inducing cellular injury and microvascular occlusion. The aim of this thesis was to conduct an animal safety study using two second generation photosensitizers, talaporfin sodium and verteporfin, to assess the risks of pancreatic PDT by looking at injury to organs adjacent to the pancreas and assessing recovery from PDT treatment of the pancreas. The Syrian Golden hamster animal model was used to compare the results of this research to previous work by other authors. The study design incorporated a number of additional experiments, including quantitative tissue fluorescence techniques, plasma level analysis and histopathology techniques. The methods for the animal safety study were similar to the approach used in the clinical setting and provided vital data on the likely risks and side effects of phototherapy in humans. The first study, looking at talaporfin sodium, found likely risks of duodenal injury, gastric injury and death with a limited effect on normal pancreas at photosensitizer doses likely to be employed for pancreatic cancer PDT. The second study, using verteporfin, found similar results with a more potent effect on the normal pancreas at studied drug doses. Both agents had short drug-light intervals, ranging from 15 minutes to 2 hours, reducing the need for pre-treatment hospitalization and short photosensitivity periods of about one to two weeks. Some animals suffered minor cutaneous photosensitivity injuries. A human pancreatic cancer PDT pilot study is feasible and the risks and complications should be acceptable.

No description available.