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Why PDX Are Needed for Metastatic Breast Cancer Research

by Jody Barbeau PhD, October 9, 2018 at 03:15 PM | Tags

illustration of breast cancer tumor starting to spread and metastasize to distant sites

illustration of breast cancer tumor starting to spread and metastasize to distant sitesMetastatic breast cancer is currently incurable, though preclinical research is ongoing. Generating new therapies for metastatic breast cancer requires preclinical breast cancer models which better-recapitulate important clinical features of the disease.

Patient-derived xenografts (PDX) can provide the spontaneously metastatic models which are missing from conventional xenograft collections.

Metastatic Breast Cancer

While breast cancer research and new treatment options have moved forward in recent years, incurable metastasis has so far resisted the efforts of researchers.

In breast cancer, primary tumors are not usually the main concern, as they are typically surgically resected. However, up to 30% of patients will eventually develop metastatic disease. This is usually in the form of a distant recurrence, sometimes many years after original diagnosis and primary tumor removal.

Unlike some other cancers, metastatic events in breast cancer often happen before the primary tumor is even diagnosed. This is why systemic hormone or chemotherapy is often provided after surgery to try and remove any disseminated tumor cells which could later cause metastasis.

It is currently poorly understood why these disseminated tumor cells remain clinically dormant before “reawakening”. Once a metastasis is clinically detected, the disease is considered incurable.

Treatment is currently a process of choosing a new therapy to try and reduce tumor burden, followed by a different treatment when resistance occurs. This creates today’s biggest challenge in breast cancer drug discovery - to develop new therapies which can keep metastatic disease at bay.

Developing New Metastatic Breast Cancer Therapies

A major shortcoming in developing new treatments for metastatic breast cancer is a lack of appropriate preclinical models. Researchers need models of human tumors which are both slow growing and spontaneously metastatic in order to to test new therapies for metastasis treatment and prevention.

Historic drug development has used conventional cell line-derived xenografts. However, breast cancer xenografts are poorly metastatic, possibly because they’ve “forgotten” how to interact with their environment over many decades of in vitro culture. Current xenograft models of metastasis often involve tail vein injections or intracardiac injection to try and force tumor growth at other sites.

Patient-Derived Xenograft Models of Breast Cancer

To overcome these shortfalls and to study true metastatic breast cancer, patient-derived xenografts (PDX) can be developed instead. These translational models are developed from human breast tumor cells or tissue from patients collected during a lumpectomy or mastectomy. The cells/tissues are then directly, orthotopically engrafted into the cleared mammary fat pads of immunocompromised mice, with no cell culture stage in between.

Metastatic tumor samples can also be used to develop the models. Serial transplantation in mice allows any initially limited tissue supplies to be expanded, which can be particularly important for such metastatic tumor biopsies.

Development and characterization of breast cancer PDX can be time consuming due to slow model growth. Take rates in model creation vary; some published panels have seen just under 30% success rate for model development. Positive engraftment has been shown to correlate with poor patient outcome, with models more likely to develop from disease which recurs early.

This could provide new insights on the biology of more aggressive breast tumors, but also preferentially provides models of metastatic disease.

Advantages of Breast Cancer PDX

There are many advantages to using PDX in metastatic breast cancer preclinical research (and breast cancer research in general).

PDX maintain the histology and architecture of the original tumors, as well as mostly maintaining large genomic alterations and sequence variants. Though some heterogeneity may be lost at P0 (the initial mouse passage), PDX still more-closely reflect original tumors than conventional xenografts. RNA sequencing and protein profiles (e.g. molecular subtype) are also preserved in PDX models.

As the tumors are derived from the clinical population, all breast cancer subtypes are represented within PDX panels. This includes the luminal A subtype, which are ER+, slowly proliferating tumors. ER+ PDX offer a big advantage in preclinical research, as there’s a shortage of estrogen-dependent or endocrine-resistant human breast cancer models. Studies usually fall back on xenografts such as T47D or MCF7, so having new PDX models available provides a wealth of more translational options. For ER+ PDX tumors, model growth can be supplemented with estrogen pellets.

For drug development purposes, the growth of PDX tumor models can also be synchronized across a large cohort of models, allowing for easy efficacy testing of drugs in vivo.

Metastasis in PDX Models

Most importantly, breast cancer PDX spontaneously metastasize within immunocompromised mice, allowing human disease-relevant studies. Metastases are often seen in sites such as the lung and lymph nodes, but also in bone, ovaries, and the peritoneum. Pairs of models can be generated from the same patient which cover primary and metastatic disease, as well as multiple models from a patient over the course of their progressive metastasis treatment (including disease sensitive/resistant models).

Summary

Within breast cancer drug development, incurable metastatic disease has a high unmet need for new treatments and new preclinical models to help develop them. Patient-derived xenografts which spontaneously metastasize and cover all breast cancer subtypes provide a more translational option for rapidly progressing metastatic disease drug discovery programs.


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