The forthcoming annual meeting of the American Association for Cancer Research (AACR) in Washington DC is a must attend for anyone interested in cancer research and new cancer drugs in development.
Many readers will know that one of the hallmarks of cancer is the evasion of apoptosis or cell death. Drugs in development that act as an inhibitor of apoptosis proteins (IAP) are starting to show promise against this target.
Novartis IAP Inhibitor LCL161
At the 2012 San Antonio Breast Cancer Symposium (SABCS), a phase 1 trial with LCL161, a novel-IAP antagonist from Novartis, showed promising responses in triple negative breast cancer when given in combination with paclitaxel chemotherapy. The SABCS data showed that in the 52 patients treated with LCL161, a complete response was observed in 1 patient, and a partial response was seen in 15 patients.
Caution must obviously be expressed at extrapolating from early-stage data in a non-randomized trial.
Several other companies have IAP antagonists in early development, including Curis (CUDC-427).
- Curis announced in November they had licensed GDC-0917 from Genentech. I am hopeful there will be new data on CUDC-427 at the AACR annual meeting. At the recent Citi Global Healthcare Conference on Feb 25, 2013, Curis stated they could start phase 2 development of CUDC-427 by mid-2013 and were looking at it in combination with capecitabine (Xeloda) in breast cancer as well as monotherapy.
- Ascenta Therapeutics licensed their IAP inhibitor AT-406 to Debiopharm in August 2011.
Nature Reviews Drug Discovery has a review article on “Targeting IAP proteins for therapeutic intervention in cancer” for those interested in learning more about some of the compounds in preclinical and clinical development, and the scientific rationale behind this target.
IAP inhibitors are an interesting class of compounds to watch as they move forward in clinical development.
IAP Inhibitors may promote Bone Metastasis
Research published in the February 2013 issue of the AACR journal Cancer Discovery shows that in mouse experiments a side-effect of IAP inhibitors is promotion of osteoclast activity. Whether these preclinical results in animal models translate to man remains to be seen, but the research by Chang Yang and colleagues from the Washington University School of Medicine in St Louis, MO is worth noting.
In simple terms, osteoclasts are the cells that remove bone as part of a dynamic equilibrium with osteoblasts, the cells that produce and lay down new bone.
An increase in osteoclasts caused by IAP antagonists activating alternative NF-κB signalling through NF-κB-inducing kinase (NIK) results in the disruption of normal bone metabolism. In mouse experiments, this led to over-degradation of bone and osteoporosis (pathological bone loss), as well as providing a microenvironment that favors tumor expansion and metastasis.
Osteoclasts embedded in the bone matrix also release tumor growth factors, so if there are more osteoclasts then more growth factors are produced resulting in the creation of a more favourable microenvironment for bone metastasis.
In addition to showing the effects of IAP antagonists on the bone microenvironment, Chang Yang and colleagues demonstrated that drugs that prevent bone resorption such as zoledronic acid were able to decrease the incidence and severity of bone metastasis.
Many breast, cancer, prostate and lung cancer patients end up with bone metastases, which is why bone targeted agents have an important role to play in the treatment of the disease.
They conclude in their Cancer Discovery research paper that “future clinical trials of IAP antagonist-based therapy may require detailed examination of this potential for enhanced bone metastasis and osteoporosis, as well as possible combination with antiresorptive agents.”
The potential implications of this research is that bisphosphonates such as zoledronic acid and RANKL-targeted compounds, such as denosumab, may need to be used in conjunction with IAP antagonist treatment.
This is an important finding. If the animal results translate to humans, then concomitant administration of a bone target agent may be necessary. Future clinical trials of IAP antagonists could end up with more complex and expensive study designs if bone side effects needs to be monitored and addressed.
I look forward to learning more about IAP antagonists at the AACR meeting in April, and to following progress in this novel class of new drugs that seek to address one of the hallmarks of cancer.
Yang, C., Davis, J., Zeng, R., Vora, P., Su, X., Collins, L., Vangveravong, S., Mach, R., Piwnica-Worms, D., Weilbaecher, K., Faccio, R., & Veis Novack, D. (2012). Antagonism of Inhibitor of Apoptosis Proteins Increases Bone Metastasis via Unexpected Osteoclast Activation Cancer Discovery, 3 (2), 212-223 DOI: 10.1158/2159-8290.CD-12-0271