Abstract Number: 979
The anti-tumor activity of the Smoothened inhibitor IPI-926 in models of residual disease is time dependent
Although response rates can be high for some solid tumors and hematologic malignancies following treatment, cure rates are low and there is a need to extend the duration of response and overall survival after remission. This relapse is attributed to the presence of residual malignant cells that remain undetected after primary treatment and in many instances the presence of these residual tumor cells eventually leads to disease recurrence and shortened survival.
The role of the Hedgehog (Hh) pathway in cancer has been well established, with both ligand-independent signaling due to genetic mutations, as well as ligand-dependent signaling, in which Hh signaling occurs either directly to the tumor cells or to the tumor microenvironment being observed. Moreover, it has been shown that Hh ligand produced by tumor cells acts on stromal cells and inhibition of this interaction results in alterations to the tumor-associated stroma and significant inhibition of tumor growth.
IPI-926 is a potent and selective Hh pathway antagonist that inhibits the key signaling membrane protein Smoothened (Smo). IPI-926 delays tumor regrowth post-cytoreduction with either standard of care chemotherapy or targeted therapy in pre-clinical xenograft models of small cell lung (SCLC), non-small cell lung (NSCLC) and prostate cancer. Data reported here show that the activity of IPI-926 in this post-therapy setting exhibits a strict time-dependence, or “efficacy window”. In both the Lx-22 SCLC and H1650 NSCLC models, delaying the time between cytoreductive therapy and initiation of IPI-926 treatment resulted in significant loss of anti-tumor activity. To investigate the molecular consequences underlying this loss of activity, RT-PCR analysis of tumors from different time points post therapy was performed. These results showed upregulation of human Hh ligand in the tumors in response to cytoreductive therapy with subsequent increased Hh signaling in the murine-derived stromal cells. IPI-926 abrogated this signaling. In addition, histological and immunohistochemical analysis demonstrated that IPI-926 induced significant changes in the tumor microenvironment post therapy. Taken together, these data suggest that the administration of IPI-926 post cytoreductive therapy could potentially be beneficial in the residual disease setting in multiple cancer types and warrants further investigation. Moreover, the timing of IPI-926 administration post therapy is critical for this benefit. IPI-926 is currently being evaluated in three Phase 2 clinical trials designed to explore multiple approaches to target ligand-dependent activation of the Hh pathway: 1) a randomized Phase 2 trial in combination with gemcitabine in patients with metastatic pancreatic cancer; 2) a randomized Phase 2 in patients with metastatic or locally advanced chondrosarcoma; and 3) a single-arm Phase 2 trial in patients with myelofibrosis.
Abstract Number: 3285
Hedgehog pathway inhibition delays regrowth of ovarian cancer following paclitaxel and carboplatinum only if initiated immediately after completion of chemotherapy
The high mortality associated with ovarian cancer is attributed to the lack of any reliable early detection method, unknown pathogenesis of the disease, and the development of recurrent and chemoresistant tumors. Current efforts have focused on the identification of therapeutics that may be used independently or in combination with current chemotherapeutic regimens to reduce tumor volume. To date, limited research has focused on preventing or delaying disease recurrence. The Hedgehog (Hh) signal transduction pathway is inactive in most adult cells. Malignant activation of the Hh pathway through the signaling protein Smoothened (Smo) occurs in a broad range of cancers, including ovarian. IPI-926 is a potent orally delivered small molecule that targets the Hh pathway by inhibiting Smo. Recent studies from our laboratory provide evidence that IPI-926 slows serous ovarian cancer growth in a primary human tumor xenograft model. More importantly, IPI-926 delays the resurgence of tumor growth typically observed after cytoreduction with paclitaxel and carboplatinum (T/C) treatment.
Our current objective was to assess whether this effect of IPI-926 required that the Smo inhibitor be administered during a critical window following T/C treatment to prevent the resurgence of tumor growth. To test our hypothesis, mice bearing human ovarian cancer xenografts were treated with vehicle or T/C. T/C treatment was withdrawn following significant reduction (30-50%) in tumor volume. The original vehicle treated cohort was divided into 2 arms which then either received IPI-926 or continued on vehicle for the duration of the experiment. Mice in the T/C cohort were divided into 3 groups. Group 1 received vehicle alone (T/C-Vehicle), group 2 received IPI-926 immediately following the last T/C dose (T/C-IPI-926) and group 3 received no vehicle or IPI treatment for 14 days following the last T/C dose (Window). Group 3 was then maintained on IPI-926 treatment starting at day 15 post-T/C withdrawal.
The withdrawal of T/C led to a dramatic increase in tumor volume in the T/C-Vehicle group. As previously observed, tumor growth inhibition was maintained in mice receiving IPI-926 immediately following the cessation of T/C treatment. In contrast, delaying the administration of IPI-926 following T/C prevented the suppression of tumor growth as evidenced by the increased tumor volume.
Our data suggest that blocking Hh pathway activity immediately following chemotherapy maintains and prolongs the inhibitory effect of chemotherapy on ovarian tumor growth. The absence of an IPI-926-mediated inhibition of tumor resurgence following a 14-day delay in treatment supports the concept that there is a critical period for tumor re-establishment. Our data, along with those of others, suggest that the early stages of ovarian tumor re-growth may be dependent on Hh pathway signaling.