Combination drug therapy is a widely used paradigm for managing numerous human malignancies. In cancer treatment, additive and/or synergistic drug combinations can convert weakly efficacious monotherapies into regimens that produce robust anti-tumor activity. This can be explained in part through pathway interdependencies that are critical for cancer cell proliferation and survival. However, identification of the various interdependencies is difficult due to the complex molecular circuitry that underlies tumor development and progression. Here, we present a high-throughput platform that allows for an unbiased identification of synergistic and efficacious drug combinations. In a screen of 22,737 experiments of 583 doublet combinations in 39 diverse cancer cell lines using a 4 by 4 dosing regimen, both well-known and novel synergistic and efficacious combinations were identified. Here, we present an example of one such novel combination, a Wee1 inhibitor (AZD1775) and an mTOR inhibitor (ridaforolimus), and demonstrate that the combination potently and synergistically inhibits cancer cell growth in vitro and in vivo. This approach has identified novel combinations that would be difficult to reliably predict based purely on our current understanding of cancer cell biology.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Tumor hypoxia has been attracting increasing attention in the fields of radiation biology and oncology since Thomlinson and Gray detected hypoxic cells in malignant solid tumors and showed that they exert a negative impact on the outcome of radiation therapy. This unfavorable influence has, at least partly, been attributed to cancer cells acquiring a radioresistant phenotype through the activation of the transcription factor, hypoxia-inducible factor 1 (HIF-1). On the other hand, accumulating evidence has recently revealed that, even though HIF-1 is recognized as an important regulator of cellular adaptive responses to hypoxia, it may not become active and induce tumor radioresistance under hypoxic conditions only. The mechanisms by which HIF-1 is activated in cancer cells not only under hypoxic conditions, but also under normoxic conditions, through cancer-specific genetic alterations and the resultant imbalance in intermediate metabolites have been summarized herein. The relevance of the HIF-1-mediated characteristic features of cancer cells, such as the production of antioxidants through reprogramming of the glucose metabolic pathway and cell cycle regulation, for tumor radioresistance has also been reviewed.
© The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

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The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA), was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox) was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA⁺ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells.

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On March 17, 2016 Halozyme Therapeutics (NASDAQ: HALO), a biotechnology company developing novel oncology and drug-delivery therapies,reported that it will present preclinical data from five studies at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual conference next month, including results from its ongoing research of lead investigational agent, PEGPH20, and two novel pipeline assets engineered for increased action in the tumor microenvironment (Press release, Halozyme, MAR 17, 2016, View Source [SID:1234509599]). The AACR (Free AACR Whitepaper) annual conference will take place April 17-20 in New Orleans.

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The new Halozyme research builds on previously published data demonstrating increased concentration of immune cells, immunotherapies and chemotherapies in animal models when delivered in combination with PEGPH20. The studies that will be presented at AACR (Free AACR Whitepaper) show enhanced efficacy of checkpoint inhibitors on tumor growth inhibition when treated with PEGPH20, further expanding the company’s growing body of preclinical research supporting PEGPH20’s mechanism of action and potential applicability across multiple types of cancer therapy.

In addition, Halozyme will share data from two novel Halozyme-developed pipeline assets, an immune checkpoint inhibitor that targets adenosine in the tumor microenvironment and an anti-EGFR antibody-drug conjugate.

"We are pleased to share the research of our talented scientists to build on our study of novel agents targeting the tumor microenvironment," said Dr. Helen Torley, president and chief executive officer. "This new work continues to demonstrate the potential ability of PEGPH20 to increase tumor growth inhibition and the accumulation of co-administered therapies across a range of tumor types. We are also excited to share the first details of two pipeline assets that we believe hold great promise for the future."

Dr. Torley and Halozyme Chief Scientific Officer, Dr. Michael LaBarre will host a meeting for investment professionals during the AACR (Free AACR Whitepaper) conference to review data included in the abstracts. The meeting will take place on Monday, April 18 at 4 p.m. ET (3 p.m. CT, 1 p.m. PT). The event will be webcast live through the "Investors" section of Halozyme’s corporate website and a recording will be made available following the close of the event.

To access the webcast and additional documents related to the event, please visit www.halozyme.com approximately fifteen minutes prior to the start time to register, download and install any necessary audio software. The live event may be accessed by calling (877) 410-5657 (domestic callers) or (334) 323-7224 (international callers) using passcode 987221. A telephone replay will be available after the event by dialing (877) 919-4059 (domestic callers) or (334) 323-0140 (international callers) using replay passcode 13259083.

Halozyme’s AACR (Free AACR Whitepaper) abstracts include:

PEGylated recombinant hyaluronidase PH20 enhances pemetrexed antitumor efficacy in a human non-small cell lung cancer model, Sun., April 17, 1-5 p.m. CT
Preclinical evaluation of a next-generation EGFR targeting antibody-drug conjugate that promotes regression in KRAS and BRAF tumors, Mon., April 18, 8 a.m. – noon CT
Enzymatic depletion of adenosine by PEGylated, engineered adenosine deaminase 2 (PEG-ADA2): a novel immunotherapeutic approach to treat solid tumors, Mon., April 18, 8 a.m. – noon CT
PEGPH20 increases the anticancer activity of standard chemotherapy combinations, vincristine (VIN) and D actinomycin (DACT), in a Wilms xenograft model, Mon., April 18, 1-5 p.m. CT
PEGylated recombinant hyaluronidase PH20 (PEGPH20) enhances checkpoint inhibitor efficacy in syngeneic mouse models of cancer, Weds., April 20, 8 a.m. – noon CT
About PEGPH20
PEGPH20 is an investigational PEGylated form of Halozyme’s proprietary recombinant human hyaluronidase under clinical development for the potential systemic treatment of tumors that accumulate hyaluronan. FDA granted orphan drug designation to PEGPH20 for treatment of pancreatic cancer and fast track for PEGPH20 in combination with gemcitabine and nab-paclitaxel for the treatment of metastatic pancreatic cancer.

Additionally, the European Commission, acting on the recommendation from the Committee for Orphan Medicinal Products of the European Medicines Agency, designated investigational drug PEGPH20 an orphan medicinal product for the treatment of pancreatic cancer.

On March 17, 2016 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported that new preclinical data will be presented at the American Association Of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 taking place from 16 to 20 April 2016, in New Orleans, Louisiana, USA (Press release, Innate Pharma, MAR 17, 2016, View Source [SID:1234509600]).

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These data supports the rationale of four of Innate’s clinical and preclinical programs:

One poster will present preclinical data supporting the rationale for combining an NKG2A checkpoint inhibitor with a PD-1 or a PD-L1 checkpoint inhibitor in mouse models;
One poster will present new data reinforcing the rationale for IPH4301, a first-in-class anti-MICA/B humanized antibody;
Three posters will present preclinical data on new discovery programs targeting CD73 and CD39, immune checkpoints regulating the adenosine pathway, including one poster reporting data generated by OREGA Biotech, Innate’s collaborator on the CD39 project.
Nicolai Wagtmann, Chief Scientific Officer of Innate Pharma, said: "The AACR (Free AACR Whitepaper) annual meeting is one of the major events in our field. This year, we are proud to present 5 posters, demonstrating the progress of our pipeline and the excellence of Innate Pharma’s science. These data supports the rationale and the potential of our assets, and strengthens Innate’s unique positioning in the immuno-oncology field".

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Beyond posters presentations, Innate Pharma’s team will be present with a booth (#2604) to receive its peers and the financial community at AACR (Free AACR Whitepaper).

Nicolai Wagtmann, Chief Scientific Officer of Innate Pharma, will hold a conference call to the attention of analysts and portfolio managers to discuss the data published and Company’s innovative pipeline.

Time and dial in: Tuesday, April 19th 10:30am Eastern Time

USA: 888 504 7963

International: +1 719 325 2452

Access code: 1890466

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About the posters to be presented at the AACR (Free AACR Whitepaper) Annual Meeting 2016:

IPH4301, an antibody targeting MICA and MICB exhibits potent cytotoxic activity and immunomodulatory properties for the treatment of cancer

Permanent Abstract Number: 1491
Session Category: Immunology
Session Title: Immune Modulating Agents and Therapeutic Antibodies
Session Date and Time: Monday Apr 18, 2016 8:00 AM – 12:00 PM
Location: Convention Center, Halls G-J, Poster Section 25
Presented by Mathieu Bléry, PhD
NKG2A immune checkpoint blockade enhances the anti-tumor efficacy of PD1/PD-L1 inhibitors in a preclinical model

Permanent Abstract Number: 2342
Session Category: Immunology
Session Title: Immune Checkpoints 1
Session Date and Time: Monday Apr 18, 2016 1:00 PM – 5:00 PM
Location: Convention Center, Halls G-J, Poster Section 26
Presented by Pascale André, PhD
Discovery and characterization of new original blocking antibodies targeting the CD73 immune checkpoint for cancer immunotherapy

Permanent Abstract Number: 2344
Session Category: Immunology
Session Title: Immune Checkpoints 1
Session Date and Time: Monday Apr 18, 2016 1:00 PM – 5:00 PM
Location: Convention Center, Halls G-J, Poster Section 26
Presented by Ivan Perrot, PhD
Disruption of the CD39 immune checkpoint pathway increases the efficacy of various anticancer therapies in syngeneic mouse models

Permanent Abstract Number: 3218
Session Category: Immunology
Session Title: Immune Checkpoints 2
Session Date and Time: Tuesday Apr 19, 2016 8:00 AM – 12:00 PM
Location: Convention Center, Halls G-J, Poster Section 25
Presented by Jérémy Bastid, PharmD, PhD (OREGA Biotech)
Preclinical development of a humanized blocking antibody targeting the CD39 immune checkpoint for cancer immunotherapy

Permanent Abstract Number: 3222
Session Category: Immunology
Session Title: Immune Checkpoints 2
Session Date and Time: Tuesday Apr 19, 2016 8:00 AM – 12:00 PM
Location: Convention Center, Halls G-J, Poster Section 25
Presented by Ivan Perrot, PhD