Doublet and Triplet Combinations of Eribulin, Fulvestrant, and Palbociclib in Preclinical Breast Cancer Models.

Background/aim: This study investigated in vivo synergism between eribulin and palbociclib in a breast cancer patient-derived xenograft (PDX) model, with expanded scope to include fulvestrant as a third drug.

Materials And Methods: Eribulin plus palbociclib combinations were tested in vitro in six cell lines each of estrogen receptor positive and triple-negative breast cancer, and in vivo in the OD-BRE-0192 PDX model using weekly eribulin plus 5×/week or 7×/week palbociclib (holiday or no-holiday schedules, respectively). When included as a third drug, fulvestrant was dosed weekly.

γδ-Enriched CAR-T cell therapy for bone metastatic castrate-resistant prostate cancer.

Immune checkpoint blockade has been largely unsuccessful for the treatment of bone metastatic castrate-resistant prostate cancer (mCRPC). Here, we report a combinatorial strategy to treat mCRPC using γδ-enriched chimeric antigen receptor (CAR) T cells and zoledronate (ZOL). In a preclinical murine model of bone mCRPC, γδ CAR-T cells targeting prostate stem cell antigen (PSCA) induced a rapid and significant regression of established tumors, combined with increased survival and reduced cancer-associated bone disease.

An immunoproteomic approach to characterize the CAR interactome and signalosome.

Adoptive transfer of T cells that express a chimeric antigen receptor (CAR) is an approved immunotherapy that may be curative for some hematological cancers. To better understand the therapeutic mechanism of action, we systematically analyzed CAR signaling in human primary T cells by mass spectrometry. When we compared the interactomes and the signaling pathways activated by distinct CAR-T cells that shared the same antigen-binding domain but differed in their intracellular domains and their in vivo antitumor efficacy, we found that only second-generation CARs induced the expression of a constitutively phosphorylated form of CD3ζ that resembled the endogenous species.

In vivo phosphoantigen levels in bisphosphonate-treated human breast tumors trigger Vγ9Vδ2 T-cell antitumor cytotoxicity through ICAM-1 engagement.

Purpose: Nitrogen-containing bisphosphonates (N-BP) such as zoledronate and risedronate exhibit antitumor effects. They block the activity of farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway, leading to intracellular accumulation of mevalonate metabolites (IPP/ApppI), which are recognized as tumor phosphoantigens by Vγ9Vδ2 T cells. However, mechanisms responsible for Vγ9Vδ2 T-cell recognition of N-BP-treated tumors producing IPP/ApppI remain unclear.

Bisphosphonates in preclinical bone oncology.

Bisphosphonates, especially nitrogen-containing bisphosphonates, are widely used to block bone destruction in cancer patients with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. In addition to their antiresorptive effects, preclinical evidence strongly suggests that nitrogen-containing bisphosphonates exert direct and indirect anticancer activities through inhibition of tumor cell functions, enhancement of the cytotoxic activity of chemotherapy agents, inhibition of tumor angiogenesis, and stimulation of antitumor immune reactions. This review examines the current evidence and provides insights into ongoing preclinical research on anticancer activities of these bisphosphonates in animal models of tumorigenesis and metastasis.

Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase.

Nitrogen-containing bisphosphonates (N-BPs) are widely used to block bone destruction associated with bone metastasis because they are effective inhibitors of osteoclast-mediated bone resorption. More specifically, once internalized by osteoclasts, N-BPs block the activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. In addition to their antiresorptive activity, preclinical evidence shows that N-BPs have antiangiogenic properties.

Bisphosphonates in cancer therapy.

Bisphosphonates are the standard of care in the treatment of malignant bone diseases, because of their ability to inhibit osteoclast-mediated bone destruction. We review here preclinical evidence that bisphosphonates also exert direct antitumour effects and antiangiogenic properties. Furthermore, we describe new insights on how bisphosphonates may act synergistically in combination with antineoplastic drugs or gammadelta T cells to exhibit antitumour activity.