Curis, Inc. Message Board

key in my opinion to curis is the update on cudc-907 trial data from ph1. pi3k + hdac inhibitor. third cycle of cohort 1 will be completed by tomorrow and we should have more insight. also iap inhibitor which was created by genentech will be another near term driver with asco oral abstract and start of phase 2 soon. good luck!

CUDC-907 will unlock value for cris in the next few months. look for more data on tues and wed earnings/investor conf call this week!!!!!!

ABSTRACT Clinical outcomes for patients with multiple myeloma (MM) have improved substantially since the introduction of novel agents, including the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide. However, most patients with MM eventually relapse and prognosis remains poor among patients with relapsed and/or refractory disease. Combination therapy using agents with different mechanisms of action is emerging as an attractive treatment approach in oncology to increase efficacy and/or overcome resistance to standard treatment regimens. This review discusses unmet needs in the treatment of MM and the development of histone deacetylase inhibitors as a treatment modality for MM

Cabozantinib/XL184 (Exelexis, Inc.) has demonstrated remarkable responses in kidney cancer.

Preclinical results revealed VEGF, KIT and MET inhibition in a variety of solid tumors such as thyroid, ovarian, renal, lung, liver and prostate cancers. A phase II trial demonstrated efficacy in renal cancer with a 28 % objective response rate, stable disease rate of 62 % and median progression free survival of 14.7 months. Predominant toxicities of fatigue and diarrhea were noted. Dramatic responses in bone metastases (three of four patients) make the agent especially valuable for palliation in a disease, where presence of bone metastases is a predictor of worse survival. Cabozantinib is an emerging novel agent with promising activity in advanced kidney cancer. Randomized trials are planned in comparison with standard VEGF inhibitor therapy. Defining the role of MET overexpression would help patient selection and enrich and enhance the future evaluation of this targeted novel agent.

Written by:
Vaishampayan U.
Wayne State University, Detroit, Michigan, MI 48201, USA. vaishamu@karmanos.org

Reference: Curr Oncol Rep. 2013 Apr;15(2):76-82.

isn't the real news that most are missing is the fact that their technology is working by hitting the target? seems like that is where the $$ is to be made here by proving their technology works for licensing? i am new investor but that is how i am taking the data.

i will post stuff that i find regarding exel on twitter under @srqstockpicker there at least i can post links

Approximately 70% of patients with late stage cancers metastasize to the bone. RECIST identifies these tumors as “unmeasureable” for therapeutic response assessment. Cabozantinib (CABO), a tyrosine kinase inhibitor of MET and VEGFR2, has shown promise as an effective therapy for metastatic prostate cancer to the bone. Patients treated with CABO showed a reduction in [Tc99m]-bone scan signal suggesting tumor response to treatment. Nevertheless, a return in signal to pre-treatment levels was observed in these patients following therapy completion. It has yet to be determined if the response observed in bone scans results from tumor death, changes in bone metabolism or vascular alterations in the tumor-stromal microenvironment resulting in reduced transport of the imaging tracer. The study objective was to assess tumor and bone response to CABO in an animal model of bone metastasis using a quantitative multi-modal imaging approach.
Twenty-seven male SCID mice were implanted with PC3 cell line in the right tibia. PC3 cells were transfected with a plasmid expressing a bioluminescence imaging (BLI) reporter for measuring apoptosis. When tumor volumes reached 10mm3 by MRI, mice were distributed into 2 groups: CABO at 30 mg/kg (N=13) and vehicle (N=14). Treatments were delivered by oral gavage once a day for three weeks. Starting pre-treatment, MRI and BLI were acquired every third day and CT every week. Tumor and bone volumes were monitored by manually contouring volumes of interest (VOI) on anatomical MRI and CT images, respectively. The apparent diffusion coefficient (ADC), an indirect measure of tumor cellularity, was calculated from diffusion MRI.
Mice treated with CABO were found to have significantly higher ADC values and slower growth profile than controls (p

i might start charging : )

Prostate cancer (PCa) growth is incurable once it has metastasized to the bone microenvironment (BM). The altered BM provides a permissive niche to support tumour growth, and therapeutic strategies that target tumour-bone interactions and/or restore bone homeostasis are being pursued. This demands preclinical models that faithfully replicate tumour-bone interactions, and non-invasive imaging methods to interrogate such orthotopic models in vivo, improving the accuracy of, and accelerating pre-clinical drug development. We have used a multi-modality imaging approach to assess the radiology and response of an orthotopic VCaP PCa bone metastasis model to the c-Met/VEGFR2 inhibitor cabozantinib.
Direct intratibial injection of 2x106 luc-VCaP cells into male castrate SCID mice resulted in tumour formation within 20 days. The resulting tumours deregulated normal bone function, exhibited a predominantly sclerotic phenotype and, importantly, retained a rearrangement of the ERG oncogene, the most common chromosomal abnormality found in human PCa (40-80% of cases). Mice bearing established intratibial VCaP prostate tumours were treated daily with 30mg/kg p.o. cabozantinib (n=7) or vehicle alone (n=7) for 15 days.
Semi-quantitative photon flux measures from BLI showed a 52% regression after 14 days of treatment (p=0.016). Tumour volume was quantified from T2-weighted MR images acquired from contiguous transverse 500μm slices across the leg, with an in-plane resolution of 156μm2, in which tumour hyperintensity was clearly identifiable. Mean tumour volume was significantly (p=0.038) smaller in the cabozantinib treated group after 15 days treatment (21.9 ± 5.1 mm3) compared to the vehicle cohort (104 ± 43 mm3). These data show that cabozantinib exhibits powerful anti-tumour activity in this clinically relevant model of PCa.
Diffusion weighted MR images were acquired using a 10 b-value EPI sequence, from which the apparent diffusion coefficient (ADC),

Abstract

Anti-angiogenic treatment of glioblastoma with Vascular Endothelial Growth Factor (VEGF)- or VEGF Receptor 2 (VEGFR2) inhibitors normalizes tumor vessels, resulting in a profound radiologic response and improved quality of life. This approach however does not halt tumor progression by diffuse infiltration, as this phenotype is less angiogenesis dependent. Combined inhibition of angiogenesis and diffuse infiltrative growth would therefore be a more effective treatment approach in these tumors. The HGF/c-MET axis is important in both angiogenesis and cell migration in several tumor types including glioma. We therefore analyzed the effects of the c-MET- and VEGFR2 tyrosine kinase inhibitor cabozantinib (XL184, Exelixis) on c-MET positive orthotopic E98 glioblastoma xenografts, which routinely present with angiogenesis-dependent areas of tumor growth, as well as diffuse infiltrative growth. In in vitro cultures of E98 cells, cabozantinib effectively inhibited c-MET phosphorylation, concomitant with inhibitory effects on AKT and ERK1/2 phosphorylation, and cell proliferation and migration. VEGFR2 activation in endothelial cells was also effectively inhibited in vitro. Treatment of BALB/c nu/nu mice carrying orthotopic E98 xenografts resulted in a significant increase in overall survival. Cabozantinib effectively inhibited angiogenesis, resulting in increased hypoxia in angiogenesis-dependent tumor areas, and induced vessel normalization. Yet, tumors ultimately escaped cabozantinib therapy by diffuse infiltrative outgrowth via vessel co-option. Of importance, in contrast to the results from in vitro experiments, in vivo blockade of c-MET activation was incomplete, possibly due to multiple factors including restoration of the blood-brain barrier resulting from cabozantinib-induced VEGFR2 inhibition. In conclusion, cabozantinib is a promising therapy for c-MET positive glioma, but improving delivery of the drug to the tumor and/or the surrounding tissue may be nee