The Ebb And Flow Of Therapeutic Targeting Of NFκB In Cancer

Chronic inflammation increases the risk of cancer, and anti-inflammatory drugs can have significant benefits for patients in terms of quality of life – including alleviating pain and in some cases improving survival.

A growing body of evidence from preclinical models suggests that drugs that selectively target and inhibit the function of “bottleneck” proteins, those activated by multiple inflammatory factors, may be of value for the treatment of cancers driven by inflammation. But, recent studies in animal models of breast cancer threw a spanner in the works by uncovering the different faces of targeting NFκB.

The case for NFκB inhibitors in breast cancer bone metastasis

The skeleton is home to many inflammatory mediators, and it is a known fact that cancer cells in bone utilize inflammatory factors to communicate with and disrupt the function of bone cells, in particular, the osteoclasts (bone resorbing cells) and osteoblasts (bone forming cells). Such events lead to excessive bone loss that worsens in severity as inflammation and tumor size are increased.

Our recent experiments, published in two back-to-back papers in Oncotarget and CTI, complement this hypothesis by showing that activation of IKKβ, a key component of the NFκB pathway, orchestrates the behavior of breast cancer cells in bone.

In the Oncotarget paper, we examined the role of IKKβ expressed by breast cancer only in the initiation and progression of bone metastasis. Using patient samples from primary breast carcinoma and their matched bone tumours, we first showed that IKKβ is highly expressed in breast cancer cells in the skeleton (bony cancer cells) when compared to those present in primary breast tumours from the same patient. Then, we went on to demonstrate that increasing the expression of IKKβ in human breast cancer cell-lines enhanced their ability to metastasise and grow in the skeleton, to cause bone damage and to reduce survival in mice.

It is inconceivable that IKKβ alone can contribute to all these effects. Thus, we examined the involvement of well-known cancer driver genes and proteins by mining proteomic and genomic data obtained from the breast cancer cells used in our studies. This led us to discover that IKKβ inhibited the activity of the tumour suppressor gene FoxO3a but increased the production of the pro-tumour and osteoclast-promoting VEGFA. The involvement of these factors would explain the severity of the tumour growth and bone damage that we observed in mice injected with the breast cancer cells over-expressing IKKβ.

One can imagine that IKKβ activation in healthy cells in the tumour bone microenvironment may also contribute to these effects. We addressed this issue in a follow-up paper in the bone journal, CTI. Here, we reported that pharmacological inhibition of IKKβ in either osteoclasts or osteoblasts reduced osteoclast formation and survival, enhanced osteoblast differentiation, and protected against bone damage caused by factors produced by breast cancer cells.

From the perspective of the finding of the two papers, we can conclude that disruption of the communication between cancer and host cells by IKKβ inhibition could be of value for the treatment of metastatic cancer. This finding matters because it cuts to the heart of the message that NFκB inhibitors – as both anti-inflammatory and anti-osteoclast drugs – may have potential therapeutic efficacy in advanced cancer patients.

Targeting IKKβ in cancer: cause for concern?

A cause for cautious optimism is an observation that the role of inflammation in cancer, it seems, is not always bad. It is well known that immune cells use pro-inflammatory mediators to reduce tumour growth. A recent study published in Cancer Research showed that sustained activation of IKKβ inhibited the growth of and induced dormancy in hormone sensitive breast tumours in mice. Although the authors of this study went on to show that IKKβ  activation at a later stage of the disease enhanced the ability of the dormant breast cancer cells to metastasise (in agreement with our findings), their research is a cautionary example of how manipulation of inflammatory mediators such as NFκB can affect cancer initiation and metastasis differently depending on the type of cancer studied and stage of the disease.

The finding of the three papers, to me, is the beginning of a different way of thinking about the therapeutic targeting of the pro-inflammatory IKKβ/NFκB pathway for the treatment of cancers in organs such as the skeleton where inflammation plays a key role in tissue homeostasis. More generally, this research challenges the idea that inflammation in cancer is bad, and the main purpose of inflammatory responses in the tumour microenvironment is to promote tumour initiation and progression.

What next? With more preclinical studies in models of inflammation-driven cancers, researchers, ourselves included, could gain a better understanding of the role and consequences of targeting the action of inflammatory mediators expressed by cancer and/or healthy cells in the tumour microenvironment. We are the first to stress that it is early days, and that our so-called “superior“ anti-inflammatory drugs – such as NFκB inhibitors – need to be rigorously tested in different preclinical models of metastatic cancers.

These findings are described in the articles entitled Regulation of breast cancer induced bone disease by cancer-specific IKKβ, recently published in the journal Oncotarget, and Pharmacological Inhibition of the Skeletal IKKβ Reduces Breast Cancer-Induced Osteolysis, recently published in the journal Calcified Tissue International. This work was conducted by Silvia Marino, Ryan T. Bishop, and Aymen I. Idris from the University of Sheffield, and Patrick Mollat from Galapagos SASU.