GDF15 elevation

The study underscores the potential of GDF15 as a target for novel therapeutic interventions in prostate cancer treatment and prevention. These findings illuminate GDF15's multifaceted role in prostate cancer pathogenesis and suggest its viability as a therapeutic target.

Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC.

Cancer-related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF-15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life.

Taken together, our data suggested a protective mechanism of elevated GDF-15 in DN through obstruction of ubiquitin degradation of IKK by inhibiting NEDD4L expression, thus decreasing the activation of NF-κB and relieving the inflammation. GDF-15 could serve as a potential therapeutic target for DN.

Ponsegromab was well tolerated, suppressed serum GDF-15 concentrations, and demonstrated preliminary evidence of efficacy These findings support the continued development of ponsegromab for the treatment of cachexia.

In participants with advanced cancer, cachexia, and elevated baseline GDF-15, ponsegromab was well tolerated and suppressed serum GDF-15 concentrations to below the median concentration seen in healthy subjects. Preliminary evidence of efficacy, including a mean observed weight gain of approximately 6.5% at 12 weeks, supports continued development of ponsegromab for the treatment of cancer cachexia. Funded by Pfizer.

A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity and gait measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy scores; anorexia/appetite, nausea, vomiting, and fatigue evaluated according to questions from the Cancer-related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs, and electrocardiogram abnormalities.ClinicalTrials.gov identifier: NCT05546476

P1, N=86, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

True and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME.

Moreover, treatment with diltiazem in tumor-bearing mice also decreases cancer metastasis and nodule formation, with more GDF-15 expression in diltiazem-treated mice than saline-treated mice, respectively. These findings suggest that diltiazem regulates EMT and cell motility through elevating GDF-15 expression in breast cancers in vitro and in vivo.

P1, N=86, Recruiting, National Cancer Institute (NCI) | N=20 --> 86 | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022

In two independent melanoma patient cohorts treated with nivolumab or pembrolizumab low baseline serum GDF-15 levels were predictive for clinical response to anti-PD1 treatment and superior OS . Taken together our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into tumor tissues . Neutralizing GDF-15 with CTL-002 restores the ability of T cells to extravasate blood vessels and enter tumor tissue bothin vitro and in vivo . In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy .

P1, N=20, Recruiting, National Cancer Institute (NCI) | N=86 --> 20

In nonhuman primates, mAB1 treatment attenuates anorexia and emesis. These results suggest that GDF-15 neutralization is a potential therapeutic approach to alleviate chemotherapy-induced side effects and improve the quality of life.

Elevated plasma GDF-15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment-naïve cancer patients. GDF-15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF-15 represents a promising target for our pathophysiologic understanding in cardio-oncology linking conditions of both cardiac and neoplastic disease.

Two independent melanoma patient cohorts (88 and 34 patients) treated with nivolumab or pembrolizumab were analyzed regarding baseline GDF-15 serum levels, correlation with clinical response and overall survival. GDF-15 is elevated in serum and tumor tissue of various major cancer types. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. In addition, intratumoral GDF-15 levels in melanoma brain metastasis correlate inversely with CD3+ and CD8+ T cell infiltration.

Our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into the tumor tissue. Neutralizing GDF-15 with a proprietary antibody (CTL-002) restored the ability of T cells (especially CD8+-T-cells) to extravasate blood vessels and enter tumor tissue both in vitro and in vivo. As it is known that presence of tumor-infiltrating lymphocytes correlates with better patient outcomes in a multitude of cancers and is a predictor of response to checkpoint inhibitors, high levels of GDF-15 in the tumor may contribute to failure of immunotherapies and poor overall survival.

APG-115 in combination with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in several tumor types. The phase II study is ongoing in the cancer patients with specific bio-marker profiling.