Our technology

HOX genes

The HOX genes are a family of genes that were originally identified due to their pivotal roles in early development. They are silenced in most cells before birth, but are reactivated in a wide range of cancers, where they have been shown to be important for cancer cell survival and proliferation.


Core technology

HOX genes are an important family of genes encoding HOX proteins that control cell and tissue growth in the embryo. After birth, these genes are normally silenced, however, they can be reactivated in tumours whereby they have a role in promoting cancer cell proliferation and survival. Importantly, in cancer, these genes are not mutated but overexpressed or 'switched on' and act through partnership with other proteins to drive cancer proliferation. We have shown HOX gene dysregulation is very common in many cancers, and therefore offers a rational target for new drug development.

There are no effective ways of targeting HOX gene dysregulation in cancer cells for therapeutic benefit based on silencing aberrant expression of single genes. Although this is achievable using, for example, siRNA, this single gene approach is therapeutically ineffective due to the high level of functional redundancy amongst HOX proteins since other HOX genes take over the function of the one inhibited. There has been a general difficulty in producing effective small molecule inhibitors against transcription factors and this has proven to be a significant barrier to this approach.

There are multiple HOX proteins in cancer cells that have similar functions. We have demonstrated that the activity and specificity of HOX proteins is facilitated by their interaction with another group of proteins known as PBX, which form strong complexes with HOX proteins and are necessary for their cancer-promoting activity. The interaction between HOX and PBX proteins is therefore a clear therapeutic target as this dimerization is mediated by a highly conserved hexapeptide sequence in HOX proteins and a hydrophobic binding pocket within PBX.

Our innovation was the design and testing of a set of peptide inhibitors that employ the hexapeptide sequence to act as a competitive antagonist of HOX/PBX binding.

Accordingly, Professor Morgan developed HXR9, a short peptide that acts as a competitive antagonist of HOX/PBX binding. HXR9 was first shown to be cytotoxic to melanoma cell lines and then shown to inhibit the growth of a range of tumour types in mice. HXR9 has been superseded by HTL’s lead peptide compound HTL-001 which is more effective than HXR9 and has a more attractive pharmaceutical profile.

A key therapeutic strategy in cancer is the inhibition of proteins in the cell that promote proliferation and survival. There are multiple HOX proteins in cancer cells that have similar functions. Professor Morgan has demonstrated that the activity and specificity of HOX proteins is facilitated by their interaction with another group of proteins known as PBX. PBX proteins form strong complexes with HOX proteins and are necessary for their cancer-promoting activity. The interaction between HOX and PBX proteins is therefore a clear therapeutic target. Accordingly, Professor Morgan developed HXR9, a short peptide that acts as a competitive antagonist of HOX/PBX binding. HXR9 was first shown to be cytotoxic to melanoma cell lines and then shown to inhibit the growth of a range of tumour types in mice. HXR9 has been superseded by HTL’s lead peptide compound HTL-001 which is more effective than HXR9 and has a more attractive pharmaceutical profile.

While peptides can be highly targeted in their activity, they are naturally broken down in the gastrointestinal tract and therefore are typically restricted to intravenous injection, or injection directly into the tumour (intratumoural) or into the peritoneum (intraperitoneal). Each of these means of administration has therapeutic utility, but it is generally considered that small molecule compounds, which can be cheaper to produce, and which can be given orally or by IV, and continuously if necessary, have greater commercial potential. Accordingly HTL, has been actively seeking a small molecule version of HTL-001. The pharmacological challenge of creating such a molecule are substantial, as it is required to inhibit the same protein-protein interaction as the HTL-001 peptide. In 2016, HTL identified and patented a class of molecules which met these criteria and has synthesised a promising lead compound, HTL-002.

The research into HOX genes has been of considerable interest in academia, widely published in high impact journals and presented at international conferences. HOX genes as cancer targets have not, until recently, caught the attention of industry. This is partly explained by industry’s lack of focus on developmental genes. Professor Morgan, with a background in developmental biology, has studied extensively the role of HOX. Furthermore, peptides as a means of therapy have historically been of limited interest, whereas they are now very much in favour, and the potential of a small molecule version is also capturing attention. HOX Therapeutics has established a significant competitive lead, encompassing both intellectual property rights and know-how.

Development pipeline