Chemotherapy remains the only available treatment for triple-negative (TN) breast cancer, and most patients exhibit an incomplete pathologic response. Half of patients exhibiting an incomplete pathologic response die within five years of treatment due to chemo-resistant, recurrent tumor growth. Defining molecules responsible for TN breast cancer chemo-resistance is crucial for developing effective combination therapies blocking tumor recurrence. Historically, chemo-resistance studies have relied on long-term chemotherapy selection models that drive genetic mutations conferring cell survival. Other models suggest that tumors are heterogeneous, being composed of both chemo-sensitive and chemo-resistant tumor cell populations. We previously described a short-term chemotherapy treatment model that enriches for chemo-residual TN tumor cells. In the current work, we use this enrichment strategy to identify a novel determinant of TN breast cancer chemotherapy resistance [a nuclear isoform of basic fibroblast growth factor (bFGF)].
Studies are conducted using our in vitro model of chemotherapy resistance. Short-term chemotherapy treatment enriches for a chemo-residual TN subpopulation that over time resumes proliferation. By western blotting and real-time polymerase chain reaction, we show that this chemotherapy-enriched tumor cell subpopulation expresses nuclear bFGF. The importance of bFGF for survival of these chemo-residual cells is interrogated using short hairpin knockdown strategies. DNA repair capability is assessed by comet assay. Immunohistochemistry (IHC) is used to determine nuclear bFGF expression in TN breast cancer cases pre- and post- neoadjuvant chemotherapy.
TN tumor cells surviving short-term chemotherapy treatment express increased nuclear bFGF. bFGF knockdown reduces the number of chemo-residual TN tumor cells. Adding back a nuclear bFGF construct to bFGF knockdown cells restores their chemo-resistance. Nuclear bFGF-mediated chemo-resistance is associated with increased DNA-dependent protein kinase (DNA-PK) expression and accelerated DNA repair. In fifty-six percent of matched TN breast cancer cases, percent nuclear bFGF-positive tumor cells either increases or remains the same post- neoadjuvant chemotherapy treatment (compared to pre-treatment). These data indicate that in a subset of TN breast cancers, chemotherapy enriches for nuclear bFGF-expressing tumor cells.
These studies identify nuclear bFGF as a protein in a subset of TN breast cancers that likely contributes to drug resistance following standard chemotherapy treatment.

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Several antibody-maytansinoid conjugates (AMCs) are in clinical trials for the treatment of various cancers. Each of these conjugates can be metabolized by tumor cells to give cytotoxic maytansinoid metabolites that can kill targeted cells. In preclinical studies in mice, the cytotoxic metabolites initially formed in vivo are further processed in the mouse liver to give several oxidized metabolic species. In this work, the primary AMC metabolites were synthesized and incubated with human liver microsomes (HLMs) to determine if human liver would likely give the same metabolites as those formed in mouse liver. The results of these HLM metabolism studies as well as the subsequent syntheses of the resulting HLM oxidation products are presented. Syntheses of the minor impurities formed during the conjugation of AMCs were also conducted to determine their cytotoxicities and to establish how these impurities would be metabolized by HLM.

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On April 19, 2016 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), reported new data related to its GITRL-Fc immuno-oncology therapeutic candidate at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Meeting (Press release, OncoMed, APR 19, 2016, View Source [SID:1234511073]). OncoMed plans to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) for its GITRL-Fc candidate in late 2016/early 2017.

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In two poster presentations, OncoMed researchers highlighted the differentiating characteristics and preclinical efficacy of this therapeutic candidate. OncoMed’s GITRL-Fc is engineered using a novel single-gene linkerless GITR ligand trimer that binds to glucocorticoid-induced tumor necrosis factor receptor. GITRL-Fc appears to act by increasing effector T-cell activation and proliferation and reducing regulatory T-cell mediated immune suppression, resulting in a potent Th1 immune response. Single-agent GITRL-Fc demonstrated profound anti-tumor activity in multiple syngeneic mouse tumor models and achieved statistically significantly greater anti-tumor activity compared with GITR agonist antibody. Notably, GITRL-Fc did not induce the broad release of cytokines in the plasma and spleen observed with the GITR agonist antibody, suggesting the potential for an improved safety profile relative to agonist antibodies.

"We believe our approach to GITR activation, using the human ligand trimer that binds to the GITR receptor, will result in more effective activation and a more specific and potent immune response compared to other approaches. In a series of preclinical studies presented at the AACR (Free AACR Whitepaper) Annual Meeting, OncoMed’s GITRL-Fc demonstrated superior anti-tumor activity to an agonist antibody and induced complete tumor regressions as a single agent. Further, the broad cytokine release observed with GITR agonist antibodies was not observed using the GITR ligand approach," said Austin Gurney, PhD, co-Chief Scientific Officer and Senior Vice President, Molecular and Cellular Biology.

The activity of GITRL-Fc was also studied in comparison and in combination with anti-PDL1 and anti-PD1. GITRL-Fc combined with either anti-PDL1 or anti-PD1 resulted in a number of complete tumor regressions and single-agent GITRL-Fc demonstrated greater anti-tumor activity than single-agent anti-PDL1 or anti-PD1. The anti-tumor activity of GITRL-Fc in combination with either anti-PDL1 or anti-PD1 reduced tumor growth beyond that of any of the agents alone. Mice "cured" with GITRL-Fc or GITRL-Fc/anti-PDL1 or GITRL-Fc/and-PD1 combination treatments were protected from re-challenge with parental tumor cells, indicating the development of sustained anti-tumor immunologic memory.

These data were presented in Abstract #2214 "GITR ligand fusion protein (GITRL-Fc) induces T cell mediated anti-tumor immune response and can combine with anti-PDL1 to enhance anti-tumor immunity and long-term immune memory" and Abstract 3215 "GITRL-Fc can significantly reduce tumor growth by stimulating innate and adaptive immunity".

On April 19, 2016 Peloton Therapeutics, Inc., a drug discovery and development company focused on advancing first-in-class, small molecule cancer therapies targeting unexploited molecular vulnerabilities, reported preclinical data on its lead investigational candidate, PT2385, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA (Press release, Peloton Therapeutics, APR 19, 2016, View Source [SID:1234511099]). PT2385 is the first clinical stage antagonist of hypoxia inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of renal and other cancers.

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"PT2385, a Novel HIF-2α Antagonist, Combines with Checkpoint Inhibitor Antibodies to Inhibit Tumor Growth in Preclinical Models by Modulating Myeloid Cells and Enhancing T Cell Infiltration"
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In addition to its direct role in transcription regulation of growth-promoting genes in renal tumors, HIF-2α has been proposed to affect the tumor microenvironment. In a poster titled "PT2385, a Novel HIF-2α Antagonist, Combines with Checkpoint Inhibitor Antibodies to Inhibit Tumor Growth in Preclinical Models by Modulating Myeloid Cells and Enhancing T Cell Infiltration," the combination of PT2385 with antibodies to immune checkpoint control molecules (PD-1, PD-L1, and CTLA4) yielded additive or synergistic efficacy in preclinical tumor models. HIF-2α is not detected in the mouse tumor cells, but is expressed in the stroma. Tumor growth inhibition by these combination regimens was accompanied by modulation of a variety of immune markers such as infiltrating T-cells, macrophage and myeloid-derived suppressor cell populations in the tumors. The combination of PT2385 and immune checkpoint inhibitors is planned for evaluation in clinical trials.

"PT2385 has now been shown to affect the tumor microenvironment, even for tumors that do not express HIF-2α. This potentially broadens the applicability of PT2385 to a larger variety of tumor types, including melanoma and lung cancers, which have been shown to have a strong immunological component," said John Josey, Ph.D., Peloton’s Chief Executive Officer.

About PT2385

PT2385 is a first-in-class small molecule inhibitor of hypoxia-inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney cancer. It is currently being investigated in a Phase 1 clinical trial for the treatment of advanced or metastatic clear cell renal cell carcinoma (ccRCC). Loss of the von Hippel-Lindau tumor suppressor (VHL) is the key oncogenic event in up to 95% of patients with ccRCC. With the loss of the VHL protein (pVHL), the transcription factor HIF-2α accumulates and drives the unbalanced expression of numerous gene products. Preclinical data indicate that orally bioavailable PT2385 disrupts HIF-2α activity in ccRCC and thereby blocks the expression of multiple tumorigenic factors responsible for unrestrained cancer cell growth and proliferation, tumor angiogenesis, and suppression of anti-tumor immune responses characteristic of ccRCC.

About Renal Cell Cancer

The American Cancer Society estimates that more than 62,000 new cases of kidney cancer will be diagnosed and more than 14,000 people will die from this disease this year. The National Cancer Institute reports that the prognosis for any treated renal cell cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage.

On April 19, 2016 Astex Pharmaceuticals, Inc., a pharmaceutical company dedicated to the development of novel small molecule oncology therapeutics, reported that it has entered into a clinical collaboration with Genentech (Press release, Otsuka, APR 19, 2016, View Source;date=2016-04-20 [SID:1234511123]).

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The collaboration will evaluate the potential for combining Astex’s next-generation hypomethylating agent, guadecitabine (SGI-110), with Genentech’s investigational anti-PD-L1 monoclonal antibody, atezolizumab, in the treatment of acute myeloid leukemia (AML). An initial Phase 1b study will investigate the safety and pharmacology of the combination.