Hedgehog Signaling: from the Cuirass to the Heart of Pancreatic Cancer

Exocrine pancreatic cancer is the fifth cause of cancer-related death in Europe and carries a very poor prognosis for all disease stages. To date no medical treatment has significantly increased patients' survival. One of the reasons for pancreatic cancer's chemoresistence is the complex tumor architecture: cancer cells are surrounded by a dense desmoplastic stroma that blocks drug delivery. Moreover, pancreatic cancer is characterized by a marked heterogeneity of cells, including cancer stem cells (CSCs) that act as tumor-initiating cells and hierarchically control the differentiated cancer cells. In particular, this subpopulation is resistant to classic cytotoxic therapies, and seems to be responsible for disease renewal. Hedgehog signaling (HH) is implicated in pancreatic gland development during\ud embryogenesis and is reactivated during tumorigenesis and the maintenance of pancreatic cancer. Some studies demonstrated that the Hedgehog-secreted signaling proteins are overexpressed in both the stromal and CSCs pools, implying an abnormal activation of HH in the main compartment of pancreatic cancer. For this reason, the Hedgehog pathway could be an interesting target for clinical trials to increase drug concentration in neoplastic cells and hence deplete the stroma and directly kill tumor-initiating cells

Impressive long-term disease stabilization by nilotinib in two pretreated patients with KIT/PDGFRA wild type metastatic gastrointestinal stromal tumors.

KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumours (GISTs) showed a response rate to imatinib ranging from 0 to 25%. Nilotinib is a new-generation tyrosine kinase inhibitor that has demonstrated clinical activity in pretreated GIST patients. At present, no correlation between nilotinib activity and clinical/pathological/molecular features is available. We report on two WT GIST patients resistant to imatinib and sunitinib, and enrolled in the CAMN107A2201 study who achieved an impressive disease control by nilotinib. Both patients have germ-line mutations in the SDHA gene. In April 2004, a 39-year-old woman presented gastric GIST with multiple liver metastases and was treated with imatinib 400 mg/day, followed by imatinib 800 mg/day and then sunitinib. In August 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. In March 2005, a 27-year-old woman started imatinib 600 mg/day and then sunitinib for gastric GIST with multiple liver and lung metastases. In October 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. One patient still showed stable disease after 46 months of treatment according to the Response Evaluation Criteria In Solid Tumors, and a partial response after 9 months according to Choi's criteria. The other patient still showed stable disease after 42 months according to Response Evaluation Criteria In Solid Tumors. At present, they continue to receive nilotinib. We report very long-term disease stabilization under nilotinib treatment in two pretreated WT GIST patients. In-vitro studies and clinical analyses are warranted to evaluate a potential correlation between nilotinib activity and WT genotype or other clinical/pathological features

Gemox in combination witherlotinib (E) in pancreatic cancer (PC).

Context: We report a case of clinical benefit and metabolic response to GEMOX and E. Case report: In November 2007 a 48-year-old woman was admitted to the our Oncology Unit for a suspected PC with a doubtful lung lesion on the basis of a CT carried out following the appearance of the abdominal pain and alteration of CA19.9 (1719 U/mL). A biopsy of pancreatic lesion documented an infiltrating pancreatic ductal adenocarcinoma. In December patient underwent exploratory laparotomy but due to the infiltration of the main vascular structures only a diagnostic laparotomy was possible. The clinical conditions were compromised (ECOG 2). CA19.9 was 21.890 U/mL. The patient started on a chemotherapy (CHT) with gemcitabine 1000 mg/m2/d1 and oxaliplatin 100 mg/m2/d2 every 2 weeks (GEMOX). After 3 cycles of CHT a CT showed a reduction in size of the pancreatic lesion (4.4 x 3.3 cm to 2.8 x 2.6 cm), a doubtful liver lesion, a stable lung lesion and multiple bone thickening lesions. CA19.9 was 8,942 U/mL. In February a PET showed a hyperfixation of tracer in pancreatic head, left lung and at the level of multiple segments of bone compatible with secondary lesions. The clinical conditions worsened. Therefore patient started on GEMOX combined with E 100 mg daily and also Zoledronic acid. After 6 cycles of CHT, a CT showed an important reduction of the lung lesion, compatible with a primary neoplasm; the bone lesions were stable and the pancreatic lesion was further reduced. A subsequent PET showed a minimal residual disease at the bone level only. The clinical conditions improved significantly (ECOG 0). CA 19.9 was 1382 U/mL. Conclusion: This is the first case reported in literature in which was used the combination of GEMOX and E