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Nuclear basic fibroblast growth factor regulates triple-negative breast cancer chemo-resistance.

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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MicroRNA profiling of the pubertal mouse mammary gland identifies miR-184 as a candidate breast tumour suppressor gene.

The study of mammalian development has offered many insights into the molecular aetiology of cancer. We previously used analysis of mammary morphogenesis to discover a critical role for GATA-3 in mammary developmental and carcinogenesis. In recent years an important role for microRNAs (miRNAs) in a myriad of cellular processes in development and in oncogenesis has emerged.
microRNA profiling was conducted on stromal and epithelial cellular subsets microdissected from the pubertal mouse mammary gland. miR-184 was reactivated by transient or stable overexpression in breast cancer cell lines and examined using a series of in vitro (proliferation, tumour-sphere and protein synthesis) assays. Orthotopic xenografts of breast cancer cells were used to assess the effect of miR-184 on tumourigenesis as well as distant metastasis. Interactions between miR-184 and its putative targets were assessed by quantitative PCR, microarray, bioinformatics and 3′ untranslated region Luciferase reporter assay. The methylation status of primary patient samples was determined by MBD-Cap sequencing. Lastly, the clinical prognostic significance of miR-184 putative targets was assessed using publicly available datasets.
A large number of microRNA were restricted in their expression to specific tissue subsets. MicroRNA-184 (miR-184) was exclusively expressed in epithelial cells and markedly upregulated during differentiation of the proliferative, invasive cells of the pubertal terminal end bud (TEB) into ductal epithelial cells in vivo. miR-184 expression was silenced in mouse tumour models compared to non-transformed epithelium and in a majority of breast cancer cell line models. Ectopic reactivation of miR-184 inhibited the proliferation and self-renewal of triple negative breast cancer (TNBC) cell lines in vitro and delayed primary tumour formation and reduced metastatic burden in vivo. Gene expression studies uncovered multi-factorial regulation of genes in the AKT/mTORC1 pathway by miR-184. In clinical breast cancer tissues, expression of miR-184 is lost in primary TNBCs while the miR-184 promoter is methylated in a subset of lymph node metastases from TNBC patients.
These studies elucidate a new layer of regulation in the PI3K/AKT/mTOR pathway with relevance to mammary development and tumour progression and identify miR-184 as a putative breast tumour suppressor.

Synthesis and Preclinical Evaluation of Folate-NOTA-Al(18)F for PET Imaging of Folate-Receptor-Positive Tumors.

Folate-receptor-targeted PET radiotracers can potentially serve as versatile imaging agents for the diagnosis, staging, and prediction of response to therapy of patients with folate-receptor (FR)-expressing cancers. Because current FR-targeted PET reagents can be compromised by complex labeling procedures, low specific activities, poor radiochemical yields, or unwanted accumulation in FR negative tissues, we have undertaken to design an improved folate-PET agent that might be more amenable for clinical development. For this purpose, we have synthesized a folate-NOTA-Al(18)F radiotracer and examined its properties both in vitro and in vivo.
Radiochemical synthesis of folate-NOTA-Al(18)F was achieved by incubating (18)F(-) with AlCl3 for 2 min followed by heating in the presence of folate-NOTA for 15 min at 100 °C. Binding of folate-NOTA-Al(18)F to FR was quantitated in homogenates of KB and Cal51 tumor xenografts in the presence and absence of excess folic acid as a competitor. In vivo imaging was performed on nu/nu mice bearing either FR+ve (KB cell) or FR-ve (A549 cell) tumor xenografts, and specific accumulation of the radiotracer in tumor and other tissues was assessed by high-resolution micro-PET and ex vivo biodistribution in the presence and absence of excess folic acid. Image quality of folate-NOTA-Al(18)F was compared with that of (99m)Tc-EC20, a clinically established folate-targeted SPECT imaging agent.
Total radiochemical synthesis and purification of folate-NOTA-Al(18)F was completed within 37 min, yielding a specific activity of 68.82 ± 18.5 GBq/μmol, radiochemical yield of 18.6 ± 4.5%, and radiochemical purity of 98.3 ± 2.9%. Analysis of FR binding revealed a Kd of ∼1.0 nM, and micro-PET imaging together with ex vivo biodistribution analyses demonstrated high FR-mediated uptake in an FR+ tumor and the kidneys.
Folate-NOTA-Al(18)F constitutes an easily prepared FR-targeted PET imaging agent with improved radiopharmaceutical properties and high specificity for folate receptor expressing tumors. Given its improved properties over (99m)Tc-EC20 (i.e., higher resolution, shorter image acquisition time, etc.), we conclude that folate-NOTA-Al(18)F constitutes a viable alternative to (99m)Tc-EC20 for use in identification, diagnosis, and staging of patients with FR-expressing cancers.

SignalRx Presents at AACR Annual Meeting on First-In-Class Dual PI3K/BRD4 Inhibitors for Treating Cancer

On April 19, 2016 SignalRx Pharmaceuticals Inc., focused on developing more effective oncology drugs through molecular design imparting multiple target-selected inhibition, reported the presentation of scientific data on the company’s dual small-molecule PI3K/BRD4 inhibitor program in oncology (Press release, SignalRx, APR 19, 2016, http://www.ireachcontent.com/news-releases/signalrx-presents-at-aacr-annual-meeting-on-first-in-class-dual-pi3kbrd4-inhibitors-for-treating-cancer-576189881.html [SID1234527327]). The presentation by Dr. Donald L. Durden, MD, PhD, senior scientific advisor for SignalRx, was made at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA.

The presentation highlighted advancements in the development of SF2523, SF2535 and SF2558HA, all single small molecules that inhibit both PI3 kinase (PI3K) and the new epigenetic cancer target BRD4. Key breakthroughs are:

New crystal structures obtained for SF2523, SF2535 and SF2558HA with BRD4 protein providing insights on key dual inhibitor binding interactions.
First-time proof of MYC inhibition by enhancing MYC degradation via PI3K inhibition AND blocking MYC production via MYC transcription inhibition (BRD4 inhibition).
SF2523 exhibits desired in vivo anti-tumor effects with no toxicity in several mouse cancer models.
Inhibition of PI3K-gamma and delta isoforms by SF2523 function as checkpoint inhibitors and enhance immune-therapeutics.
BRD4 inhibition blocks tumor-specific super-enhancers activating the innate and adaptive immune response providing a novel strategy to treat cancer.
The company also demonstrated that SF2523 is safer to normal cells over the combination of single PI3K and BRD4 inhibitors making SF2523 an attractive anti-cancer candidate that can potentially overcome traditional toxicity issues associated with most combinations of oncology drugs.

SignalRx is also announcing that it is seeking a partner to accelerate the development of these novel small molecules into first-in-man clinical trials based on the promising profile of its PI3K/BRD4 inhibitors shown so far. Since these are single molecules with a single PK/PD and toxicity profile, there is a great opportunity to develop them as single therapeutics and streamline their development in combination therapies focused on companion diagnostics built around synthetic lethality discoveries in human cancers, e.g., kinome adaptation mediated by BRD4.

Astex Pharmaceuticals Enters Clinical Trial Collaboration to Explore the Potential of Combining Guadecitabine (SGI-110) with Atezolizumab in the Treatment of Acute Myeloid Leukemia

On April 19th, 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, Astex Pharmaceuticals, APR 19, 2016, View Source [SID:1234511097]).

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.

The collaboration will test the hypothesis that upfront "priming" of patients’ immune systems with guadecitabine, an epigenetic investigational drug, may result in enhanced responses to immunotherapy. The hypothesis is based on the observation that guadecitabine demethylates and induces re-expression of tumor associated antigens, as well as inducing or upregulating the expression of immune checkpoints such as programmed death 1 (PD-1), and programmed deathligand 1 (PD-L1) and 2 (PD-L2), rendering the tumor more immunogenic, and more susceptible to treatment with a checkpoint inhibitor antibody such as atezolizumab (Maio et al, Clin. Cancer Research, 2015; 21:4040-47).

Guadecitabine has been evaluated in multiple Phase 1 and Phase 2 trials to investigate its potential in the treatment of a range of cancers. Astex has recently completed a large (over 400 patients) randomized Phase 1/2 study in patients with myelodysplastic syndromes (MDS) or AML. The trial included a Phase I dose escalation stage (93 patients) and a randomized Phase 2 stage (308 patients) that investigated four different patient populations: treatment naïve and relapsed/refractory AML and MDS. The trial demonstrated that guadecitabine was clinically active and well tolerated in all four patient groups. The results from the Phase 1 portion of the trial were recently published in Lancet Oncology (http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2815%2900038-8/abstract). Additional information about the study can be found online at View Source

Guadecitabine is now being evaluated in the ASTRAL-1 trial, a large, global, randomized 800-patient study in treatment naïve AML patients who are unfit to receive, or unsuitable for, intensive induction chemotherapy. The trial compares guadecitabine with physician’s choice of low-dose cytarabine, decitabine or azacitidine. Additional information about the study can be found online at: View Source

Mohammad Azab, Astex’s President and Chief Medical Officer said: "We are delighted that Genentech has chosen to partner with Astex on this exciting study. The idea of combining epigenetic therapies such as guadecitabine with immune checkpoint inhibitors such as atezolizumab, has the potential to open up new therapeutic options with enhanced outcomes for patients with a range of cancer types. Astex is committed to exploring the broad potential of guadecitabine as a "backbone" therapy for use in immunotherapy combinations.

About Acute Myeloid Leukemia (AML)
AML is the most common form of leukemia in adults. Over 20,000 new cases of AML are diagnosed annually in the US. Although 60%-75% of AML patients 60 years old is significantly worse with response rates < 50%, cure rates remaining at <10% and a median survival of 1 year. These figures have not significantly improved within the last 3 decades. These patients have few therapeutic options. Effective, less toxic therapies are needed for the treatment of AML, particularly for elderly patients whose comorbidities make them unfit for intensive therapy.

About Guadecitabine (SGI-110)

Guadecitabine is a novel next-generation, small molecule DNA hypomethylating agent formulated as a single, small volume, subcutaneous injection. The product was designed to deliver longer exposure to the active metabolite, decitabine, compared to iv decitabine, and more efficient delivery into key tissues, including the bone marrow. Guadecitabine demonstrated activity in restoring silenced tumor suppressor gene expression in cancer cells by reversal of DNA methylation and inducing responses in previously treated MDS and AML patients. Guadecitabine is wholly owned by Astex Pharmaceuticals.

About Atezolizumab
Atezolizumab (also known as MPDL3280A) is an investigational humanized monoclonal antibody designed to target and bind to a protein called PD-L1, which is expressed on tumor cells and tumorinfiltrating immune cells. PD-L1 interacts with PD-1 and B7.1, both found on the surface of T cells, thereby inhibiting T cell function. By blocking this interaction, atezolizumab may enable the activation of T cells, restoring their ability to effectively detect and attack tumour cells. Atezolizumab is being developed by Genentech (South San Francisco, CA, USA), a member of the Roche Group.