Humanized Mice in Cancer Bone Metastasis Studies


     
Osteoporosis stage 3 of 4 - upper limb bones Despite recent advances in cancer research and drug development, bone metastases remain incurable. Some of the most common cancers, such as breast, prostate, lung, and multiple myeloma frequently metastasize to bone1,2,3.

As bone metastasis is difficult to treat and target, and because the bone itself is noted to induce drug resistance, the preclinical evaluation of new therapies in more translatable bone metastasis models may increase the likelihood of developing effective treatments2.

Immuno-Oncology and Bone Metastasis

Immuno-oncology is the newest field of cancer drug discovery. Current immunotherapies target checkpoint inhibitors, such as anti-PD-1, and many more are being validated in clinical trials.

Immuno-oncology drugs work by unlocking the immune system's ability to attack cancer by overcoming the main defense mechanisms of cancer cells. As these antibody-based immuno-oncology therapies require human immune cells to work effectively, even a minimal variance across species in the target protein can present challenges in finding the right animal model.

In order to study the efficacy and safety of these drugs, an in vivo model possessing human immune cells, such as T cells, would be ideal for efficacy evaluation in preclinical testing.

Developing Humanized Models of Bone Metastasis

There are two major methods for transplanting a human immune system into animal models: engraftment of peripheral blood mononuclear cells (PBMC) or hematopoietic stem cells (HSCs).

While huPBMC-NOG models can be utilized for testing immuno-oncology directed therapies for bone metastasis, HSC engrafted HIS mouse models such as huNOG may be more ideal. This is because bone marrow is the homing site of HSCs in mice and in humans, and the location of hematopoiesis. In a healthy state, the bone is filled with immune cells, such as B cells undergoing maturation.

Despite the presence of lymphocytes in the periphery, the huPBMC model will not mimic lymphocyte development in the bone marrow. In contrast, HSC engrafted HIS mice (huNOG and huNOG-EXL) will mimic the aspect of co-existence of HSC and cancer metastasis in the bone. Historically, cancer researchers placed large emphasis on tumor-driven hone loss (osteolysis) caused by increased osteoclast activity: this is also known as self perpetuating 'vicious cycle' proposed by Mundy and Guise4. Recently, immune cells in the bone has been getting attention as other players which may be modulating tumor growth in the bone5, huNOG would allow researchers to study such anti/pro-tumor effects of various human immune cell populations as well as cross talk between tumor and bone microenvironment involved in the bone metastatic process.

Webinar: A Novel Model for Studying Bone Metastasis

Pharmatest Services Ltd, a global contract research organization (CRO), specializes in preclinical cancer-induced bone metastasis models. In this webinar, sponsored by Taconic Biosciences, Pharmatest reports the development of a novel in vivo model of bone metastasis with huNOG mice, providing a platform for immuno-oncology drug discovery and efficacy evaluation in cancer bone metastasis research.

References:
1. Cassimiro et al., Molecular Mechanism of Bone Metastasis: Which Targets Came from the Bench to the Bedside? Int J Mol Sci, 2016.
2. Weidle et al., Molecular Mechanism of Bone Metastasis, Cancer Genomics & Proteomics, 2016.
3. Futakuichi et al., Heterogeneity of tumor cells in the bone microenvironment, Advanced Drug Delivery Reviews, 2016.
4. Mundy et al., Hypercalcemia of malignancy. American Journal of Medicine. 1997.
5. Capietto et al., Immune regulation of bone metastasis, BoneKEy, 2014.