Cancer drug discovery has traditionally focused on targeting DNA synthesis and cell division, resulting in drugs that show efficacy, but lack selectivity for tumor cells. Hence, such drugs frequently induce severe side effects. During the last two decades key proteins in cell signaling, e.g. receptors with tyrosine kinases, have emerged as potential targets for a more rational approach to selective cancer treatment.

More recently large amounts of scientific data have demonstrated that the IGF-1 receptor can be an important target for cancer therapy since the receptor’s signaling pathway is crucial for the survival and growth of most types of cancer cells. In contrast, the IGF-1 receptor is not necessary for growth of normal cells. However, it has been a major obstacle to find molecules that selectively inhibit the IGF-1 receptor without affecting the almost identical insulin receptor. The insulin receptor is essential for glucose uptake and metabolism in normal cells, so a cross-reaction with this receptor may be connected with severe side effects. Thus, targeting the IGF-1 receptor without interfering with the insulin receptor may constitute a breakthrough in cancer therapy.

Most IGF-1 receptor inhibitors currently being developed are systemically administered monoclonal antibodies.

Notably, Axelar has discovered certain unique small-molecule compounds, which inhibit the activity and downregulate the cellular expression of the IGF-1 receptor, without affecting the insulin receptor or other major growth factor receptors.

Enclosed below are some relevant scientific publications by Axelar’s founders and other researchers, and by independent research groups. A more extensive publication list can be obtained from Axelar.

Some scientific publications by Axelar’s founders and other researchers

	•		Girnita A, Girnita L, d. Prete F, Bartolazzi A, Larsson O, Axelson M. Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Research, 64, 236-242, 2004.
	•		Menu E, Jernberg-Wiklund H, Stromberg T, De Raeve H, Girnita L, Larsson O, Axelson M, Asosingh K, Nilsson K, Van Camp B and Vanderkerken K. Effects of inhibition of the IGF-1 receptor tyrosine kinase in multiple myeloma: an in vitro and in vivo study on the 5T33MM Mouse Model. Blood 2006 Jan 15;107(2):655-60.
	•		Girnita A, All-Ericsson C, Economou M, Åström K, Axelson M, Seregard S, Larsson O, Girnita L. The insulin-like growth factor-1 receptor (IGF-1R) inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells. Clin Cancer Res, 2006 12(4), 1383-1391.
	•		Menu E, Jernberg-Wiklund H, De Raeve H, De Leenheer E, Coulton L, Gallagher O, Van Valckenborgh E, Larsson O, Axelson M, Nilsson K, Van Camp B, Croucher P, Vanderkerken K. Targeting the IGF-1R using picropodophyllin in the therapeutical 5T2 MM mouse of multiple myeloma: Beneficial effects on tumor growth, angiogenesis, bone disease and survival. Int J Cancer 2007 Oct 15;121(8):1857-61.
	•		Vasilcanu R, Vasilcanu D, Rosengren L, Natalishvili N, Sehat B, Yin S, Girnita A, Axelson M, Girnita L, Larsson O. Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and ß-arrestin1. Oncogene 2008 6;27(11),1629-1638. (Epub: 10 Sept 2007).
	•		Ekman, S., et al., Clinical Phase I study with an Insulin-like Growth Factor-1 Receptor Inhibitor: Experiences in patients with squamous non-small cell lung carcinoma. Acta oncologica 2011 Apr;50(3):441-7. Epub 2010 Aug 11.

Some scientific publications by independent research groups

	•		Conti L, Regis G, Longo A, Bernabei P, Chiarle R, Giovarelli M, Novelli F. In the absence of IGF-1 signaling, IFN-gamma suppresses human malignant T-cell growth. Blood. 2007 Mar 15;109(6): 2496-2504
	•		Fulzele K, Digirolamo DJ, Liu Z, Xu J, Messina JL, Clemens TL. Disruption of the insulin-like growth factor type 1 receptor in osteoblasts enhances insulin signaling and action. J Biol Chem. 2007 Aug 31;282(35):25649-58. Epub 2007 Jun 6
	•		Guha M, Srinivasan S, Biswas G, Avadhani NG. Activation of a novel calcineurin-mediated insulin-like growth factor-1 receptor pathway, altered metabolism, and tumor cell invasion in cells subjected to mitochondrial respiratory stress. J Biol Chem. 2007 May 11;282(19):14536-46
	•		Zhu L, Pollard JW. Estradiol-17ß regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling. Proc Natl Acad Sci (USA). October 2, 2007 vol. 104: 15847–15851
	•		Clemmons, D.R., Modifying IGF1 activity: An approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov, 2007 6(10): p. 821-33.
	•		Pollak, M., Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer, 2008. 8(12): p. 915-28
	•		Gualberto, A. and M. Pollak, Clinical development of inhibitors of the insulin-like growth factor receptor in oncology. Curr Drug Targets, 2009. 10(10): p. 923-36.
•			Klinakis, A., et al., Igf1r as a therapeutic target in a mouse model of basal-like breast cancer. Proc Natl Acad Sci U S A, 2009. 106(7): p. 2359-64.