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Repurposing Itraconazole as a Molecularl Targeted Agent for Esophageal Cancer
Background: Esophageal cancer continues to affect US veterans as the risk factors for esophageal adenocarcinoma and squamous cell carcinoma are highly prevalent in this patient population. While localized esophageal cancer can be cured with a tri-modality approach that includes neoadjuvant chemoradiation followed by esophagectomy, only those patients who achieve a pathologic complete remission to neoadjuvant chemoradiation have a 50% five-year overall survival. Those who do not achieve a pathologic complete remission or those with metastatic disease have a worse prognosis. Thus, there is a need to develop novel molecularly targeted agents for the treatment of esophageal
cancer. We have found that the Hedgehog signaling pathway, required for normal esophageal embryogenesis but silenced in the adult esophagus, is reactivated in both histologic subtypes of esophageal cancer.
Results: Using immunohistochemistry for the pathway ligand Sonic hedgehog or in situ hybridization for either Sonic hedgehog or the pathway target gene Gli1 on esophageal cancer tissue microarrays, we found that 206/346 (60%) cases were Hedgehog pathway active while normal squamous esophagus was negative. The anti-fungal agent itraconazole has previously been shown to inhibit Hedgehog signaling, and we were able to inhibit cell proliferation (cell number), Hedgehog pathway activity (quantitative real-time PCR), and VEGFR2 phosphorylation (Western blot) in vitro in OE33 esophageal adenocarcinoma cells. In a novel intraperitoneal xenograft model of liver metastases, itraconazole significantly improved overall survival in mice injected intraperitoneally with OE33 cells.
Conclusions: Based on these results we are conducting a phase 0 clinical trial administering itraconazole 300 mg po bid for 14-17 days to patients with localized esophageal cancer before neoadjuvant chemoradiation. To date, we have treated 6 patients with itraconazole and demonstrated inhibition of Hedgehog signaling by quantitative real-time PCR. It is hoped that results from this early phase trial may lead to further study and development of itraconazole as a molecularly targeted agent for esophageal cancer.
Background: Esophageal cancer continues to affect US veterans as the risk factors for esophageal adenocarcinoma and squamous cell carcinoma are highly prevalent in this patient population. While localized esophageal cancer can be cured with a tri-modality approach that includes neoadjuvant chemoradiation followed by esophagectomy, only those patients who achieve a pathologic complete remission to neoadjuvant chemoradiation have a 50% five-year overall survival. Those who do not achieve a pathologic complete remission or those with metastatic disease have a worse prognosis. Thus, there is a need to develop novel molecularly targeted agents for the treatment of esophageal
cancer. We have found that the Hedgehog signaling pathway, required for normal esophageal embryogenesis but silenced in the adult esophagus, is reactivated in both histologic subtypes of esophageal cancer.
Results: Using immunohistochemistry for the pathway ligand Sonic hedgehog or in situ hybridization for either Sonic hedgehog or the pathway target gene Gli1 on esophageal cancer tissue microarrays, we found that 206/346 (60%) cases were Hedgehog pathway active while normal squamous esophagus was negative. The anti-fungal agent itraconazole has previously been shown to inhibit Hedgehog signaling, and we were able to inhibit cell proliferation (cell number), Hedgehog pathway activity (quantitative real-time PCR), and VEGFR2 phosphorylation (Western blot) in vitro in OE33 esophageal adenocarcinoma cells. In a novel intraperitoneal xenograft model of liver metastases, itraconazole significantly improved overall survival in mice injected intraperitoneally with OE33 cells.
Conclusions: Based on these results we are conducting a phase 0 clinical trial administering itraconazole 300 mg po bid for 14-17 days to patients with localized esophageal cancer before neoadjuvant chemoradiation. To date, we have treated 6 patients with itraconazole and demonstrated inhibition of Hedgehog signaling by quantitative real-time PCR. It is hoped that results from this early phase trial may lead to further study and development of itraconazole as a molecularly targeted agent for esophageal cancer.
Background: Esophageal cancer continues to affect US veterans as the risk factors for esophageal adenocarcinoma and squamous cell carcinoma are highly prevalent in this patient population. While localized esophageal cancer can be cured with a tri-modality approach that includes neoadjuvant chemoradiation followed by esophagectomy, only those patients who achieve a pathologic complete remission to neoadjuvant chemoradiation have a 50% five-year overall survival. Those who do not achieve a pathologic complete remission or those with metastatic disease have a worse prognosis. Thus, there is a need to develop novel molecularly targeted agents for the treatment of esophageal
cancer. We have found that the Hedgehog signaling pathway, required for normal esophageal embryogenesis but silenced in the adult esophagus, is reactivated in both histologic subtypes of esophageal cancer.
Results: Using immunohistochemistry for the pathway ligand Sonic hedgehog or in situ hybridization for either Sonic hedgehog or the pathway target gene Gli1 on esophageal cancer tissue microarrays, we found that 206/346 (60%) cases were Hedgehog pathway active while normal squamous esophagus was negative. The anti-fungal agent itraconazole has previously been shown to inhibit Hedgehog signaling, and we were able to inhibit cell proliferation (cell number), Hedgehog pathway activity (quantitative real-time PCR), and VEGFR2 phosphorylation (Western blot) in vitro in OE33 esophageal adenocarcinoma cells. In a novel intraperitoneal xenograft model of liver metastases, itraconazole significantly improved overall survival in mice injected intraperitoneally with OE33 cells.
Conclusions: Based on these results we are conducting a phase 0 clinical trial administering itraconazole 300 mg po bid for 14-17 days to patients with localized esophageal cancer before neoadjuvant chemoradiation. To date, we have treated 6 patients with itraconazole and demonstrated inhibition of Hedgehog signaling by quantitative real-time PCR. It is hoped that results from this early phase trial may lead to further study and development of itraconazole as a molecularly targeted agent for esophageal cancer.
Prostate Cancer in Male Seniors, Part 2: Treatment
This article (part 2 of 2) focuses on the treatment of prostate cancer in seniors. Part 1 provided an overview of prostate cancer epidemiology, pathology, and screening in senior patients.
There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Recently, the International Society of Geriatric Oncology assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.
Note: Page numbers differ between the print issue and digital edition.
This article (part 2 of 2) focuses on the treatment of prostate cancer in seniors. Part 1 provided an overview of prostate cancer epidemiology, pathology, and screening in senior patients.
There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Recently, the International Society of Geriatric Oncology assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.
This article (part 2 of 2) focuses on the treatment of prostate cancer in seniors. Part 1 provided an overview of prostate cancer epidemiology, pathology, and screening in senior patients.
There have been no specific practice guidelines for managing prostate cancer in older adults, and the current management of older patients with prostate cancer is often suboptimal. Recently, the International Society of Geriatric Oncology assembled a multidisciplinary prostate cancer working group, which has begun offering guidelines on evidence-based treatments of prostate cancer in the geriatric population.
Note: Page numbers differ between the print issue and digital edition.
Note: Page numbers differ between the print issue and digital edition.