2O - Growth differentiation factor 15 (GDF-15) neutralization reverses cancer cachexia, restores physical performance and mitigates emesis associated with platinum-based chemotherapy

Background

Cancer cachexia is a metabolic disease characterized by unintentional weight loss, anorexia, muscle and fat wasting, fatigue and muscle weakness, chronic inflammation, all of which being contributing factors to poor quality of life and survival in patients. It’s well established chemotherapies, most often used to treat cancers are associated with adverse effects such as weight loss, emesis/nausea, leading to limited tolerability and effectiveness of treatment. GDF-15 is a cytokine reported to cause anorexia, aversion/emesis and weight loss in preclinical models and is associated with cancer cachexia and poor survival in patients. GDF-15 inhibition was effective to reverse weight loss, muscle and fat loss in mouse tumor models. Interestingly, it remains unclear whether increased skeletal muscle mass by GDF-15 inhibition results in restoration of muscle function. GDF-15 is also associated with platinum-based chemotherapy-induced adverse effects, however, a causal role for GDF-15 in mediating the emetic response has not been established.

Methods

We investigated these questions in a mouse tumor model, TOV21G and non-human primates (NHP) using a potent and selective monoclonal antibody (mAB1) that neutralizes circulating GDF-15.

Results

Treatment with mAb1 completely reversed tumor-induced cachexia including weight loss, lean and fat mass loss as well as declined muscle function and physical performance in tumor bearing mice. We show that cisplatin-induced weight loss and anorexia is GDF-15 dependent in mouse. In addition, Cisplatin induced GDF-15 circulating level and emesis in NHP and mAB1 treatment markedly attenuated cisplatin-induced emesis. Importantly, the preclinical findings are supported by patient data where we demonstrate an association between elevated circulating GDF-15 levels and platinum-based chemotherapy use.

Conclusions

Our findings indicate GDF-15 is a key regulator of cancer cachexia and chemotherapy-induced malaise. GDF-15 inhibition holds the potential as an effective therapeutic approach in combination with chemotherapy to alleviate GDF-15 mediated malaise, declined physical function and cachexia in patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Pfizer.

Funding

Pfizer.

Disclosure

Z. Wu: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. D. Bennett: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer; Shareholder/Stockholder/Stock options: Gilead Sciences. J. Brosnan: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. R.A. Calle: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. S. Collins: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. R. Esquejo: Full/Part-time employment: Pfizer. S. Joaquim: Full/Part-time employment: Pfizer. A. Joyce: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. H. Kim: Full/Part-time employment: Pfizer. B. LaCarubba: Full/Part-time employment: Pfizer. L. Lin: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. J.Y. Kim-Muller: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. M. Peloquin: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. B. Pettersen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. S. Qiao: Full/Part-time employment: Pfizer. M. Rossulek: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. G. Weber: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. B. Zhang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer; Shareholder/Stockholder/Stock options: Lilly; Shareholder/Stockholder/Stock options: Merck; Officer/Board of Directors: Board of Director and SAB member for Keystone Symposium. M. Birnbaum: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. D. Breen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer.