On April 21, 2015 SignalRx Pharmaceuticals Inc., focused on developing more effective oncology drugs though molecular design imparting selected multiple target inhibition, reported the presentation of scientific data on the Company’s proprietary dual inhibitor program in oncology (Press release, SignalRx, APR 21, 2015, http://www.ireachcontent.com/news-releases/signalrx-presents-at-10th-annual-drug-discovery-chemistry-conference-on-its-dual-kinase-epigenetic-inhibitors-for-treating-cancer-500857951.html [SID1234527330]). The presentation by Dr. Donald L. Durden, MD, PhD, co-founder and science advisor to SignalRx was made at the Tenth Annual Drug Discovery Chemistry meeting at the Hilton San Diego Resort & Spa in San Diego, California.

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The oral presentation entitled "Discovery of Dual PI3K/BRD4 (kinase/epigenetic) Inhibitors" was given during the Second Annual Epigenetic Inhibitor Discovery track of the meeting at the "Advances in BET Bromodomain Inhibitor Development" session. The presentation highlighted a novel thienopyranone molecular scaffold that selectively inhibits both PI3 kinase (PI3K) and the bromodomain protein BRD4. The presentation described how molecular modeling studies were used to identify and design SignalRx’s single small molecules that can bind and inhibit simultaneously PI3K and BRD4. While the small molecule SF2523 inhibits PI3K via ATP competitive binding at the catalytic site, BRD4 inhibition appears to take place by binding in the acetyl-lysine recognition moiety of BRD4 thus blocking BRD4’s ability to alter chromatin structure and induce transcription. Blocking the binding of BRD4 to acetylated histones within chromatin can then block the transcription of various genes that are promoting cancer cell survival and growth. Recent reports suggest that BRD4 inhibition may block cancer cell resistance arising from widespread epigenetic kinome adaptation following exposure to targeted kinase inhibitor drugs which in turn may lead to more durable anticancer effects.

The presentation also included a specific rationale for the dual PI3K/BRD4 inhibition approach in cancers driven by the key cancer promoting transcription factor MYC. MYC (both cMYC and MYCN) acts downstream of many cell receptor complexes and signal transduction pathways to activate genes that drive cancer cell growth and proliferation. To date, small molecule inhibitors of MYC have been elusive. Inhibition of PI3K enhances the degradation of the cancer promoting transcription factor MYC. Inhibition of BRD4 blocks the production of MYC; thus, a dual PI3K/BRD4 inhibitor can lead to maximal MYC extinction by inhibiting these two different mechanisms. Our approach enables us to go after cancers expected to be susceptible to maximal MYC extinction as a beneficial treatment, such as CLL, medulloblastoma, multiple myeloma, and certain ovarian cancers exhibiting elevated MYCN expression. In vivo data also showed that SF2523 (50 mg/kg 3X per week) exhibited potent antitumor efficacy and anti-metastatic effects without toxicity in renal cell carcinoma xenograft models, neuroblastoma mouse models, orthotopic pancreatic cancer model and Lewis lung cancer models. Lastly, pre-clinical in vivo proof-of-concept with SF2523 was presented showing the pharmacodynamic knockdown of both the PI3K pathway and MYC in mouse neuroblastoma tumor samples four hours after administration, confirming the dual PI3K/BRD4 inhibitory profile of lead compound SF2523. Further preclinical studies of several PI3K/BRD4 dual inhibitor thienopyranones are underway to identify and select a clinical candidate.

On April 21, 2015 OPKO Health, Inc. (NYSE:OPK) reported the online publication of a study entitled "Predicting High-Grade Cancer at Ten-Core Prostate Biopsy Using Four Kallikrein Markers Measured in Blood in the ProtecT Study" in the Journal of the National Cancer Institute (Press release, Opko Health, APR 21, 2015, View Source [SID:1234506587]). The study shows that the four kallikrein panel of biomarkers utilized in the OPKO 4Kscore Test (Total PSA, Free PSA, Intact PSA and hK2) accurately identifies risk for aggressive prostate cancer prior to prostate biopsy.

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The Prostate Testing for Cancer and Treatment (ProtecT) study is a prospective randomized controlled trial conducted in the United Kingdom for the purpose of evaluating the cost effectiveness of conventional treatments in PSA-detected, clinically localized prostate cancer. Of the 82,428 men recruited for the trial, a total of 6129 men with elevated PSA (≥3.0 ng/mL) who underwent prostate biopsy and provided an adequate blood sample were tested for the four kallikreins and their 4Kscore result was determined. The study showed that the four kallikrein panel enhanced aggressive prostate cancer detection compared with PSA and age alone. The area under the curve (AUC) for the 4K model was 0.820 (95% CI = 0.802 to 0.838) while the PSA model was 0.738 (95% CI = 0.716 to 0.761) for high-grade cancer.

"The ProtecT study is the latest in a series of peer-reviewed publications demonstrating the superior clinical value that testing with four kallikrein markers adds to risk prediction for aggressive prostate cancer compared to PSA alone," said Dr. Peter Scardino, Chair, Department of Surgery, Memorial Sloan Kettering Cancer Center. "The high level of discrimination for differentially detecting high-grade disease supports use of the four kallikrein panel as a reflex test prior to having a prostate biopsy for men with an elevated PSA."

"The 4Kscore biomarker algorithm has now been tested and published on over 20,000 men in 11 peer-reviewed publications covering multiple US and European cohorts," said David Okrongly, President of OPKO Diagnostics. "The results all demonstrated the high discrimination and favorable decision curve benefit of the 4Kscore algorithm for predicting the results of prostate biopsy pathology, as well as 20 year outcomes for risk of metastatic prostate cancer."

About Prostate Cancer

According to the World Health Organization, prostate cancer is the second most common cancer in men worldwide, with over 1.1 million men diagnosed with prostate cancer in 2012 and over 300,000 men dying from the disease. In countries like the U.S. where screening for prostate cancer with the PSA test began 20 years ago there has been a sharp increase in the number of prostate cancers detected. However, most of the prostate cancers detected are an indolent, non-life threatening form of the disease. The net result has been a decrease in prostate cancer mortality during the PSA era, but at a cost of over detection and over treatment of indolent prostate cancers.

About the 4Kscore Test

The 4Kscore is the only blood test that accurately identifies risk for aggressive prostate cancer. The 4Kscore measures the blood plasma levels of four different prostate-derived kallikrein proteins: Total PSA, Free PSA, Intact PSA and Human Kallikrein-2 (hK2). These biomarkers are combined with a patient’s age, Digital Rectal Exam (DRE) status (nodule / no nodule), and prior negative biopsy status (yes / no) using a proprietary algorithm to calculate the risk (probability) of finding a Gleason Score 7 or higher prostate cancer. The four kallikrein panel of biomarkers utilized in the 4Kscore Test is based on over a decade of research conducted by scientists at Memorial Sloan-Kettering Cancer Center and leading European institutions. The 4Kscore Test provides individualized risk for the presence of aggressive prostate cancer and adds new information to the shared decision making discussion between a Urologist and patient.

On April 21, 2015 Generex Biotechnology Corporation (www.generex.com) (OTCQB: GNBT) reported presentation of data from the on-going Phase II clinical trial of the AE37 breast cancer vaccine correlating local immune response to a reduction in relapse (Press release, Generex, APR 21, 2015, View Source [SID:1234506588]). AE37 is being developed by Antigen Express, Inc. (www.antigenexpress.com), a wholly-owned subsidiary of Generex. The presentation was made at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting held in Philadelphia, PA from April 18 to 22.

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The abstract entitled ‘Correlation of robust local reactions prompting GM-CSF dose reduction to clinical response in a Phase II trial of the AE37+GM-CSF HER2 peptide vaccine’ by Julia Greene, et al was presented at the Clinical Trials in Progress session of the AACR (Free AACR Whitepaper) on April 20. The goal of the study was to establish the importance of the local reaction to immunization with AE37. The controlled, randomized and single-blinded trial is comparing the ability of AE37 plus the adjuvant GM-CSF versus the GM-CSF adjuvant alone to reduce recurrence of breast cancer in early stage patients. The study found that those patients receiving AE37 who had the largest responses (requiring reductions in the amount of GM-CSF) had a relapse rate of 5.9% versus a rate of 14.2% in those who did not require dose reduction. This indicates that a robust stimulation of the immune system by AE37, as evidenced by the need for dose reduction, results in positive anti-cancer activity.

The AE37 vaccine is designed to activate critical components of the immune system to combat cancer cells. Prior analyses have shown a trend toward reduction of relapse in patients receiving the vaccine, particularly those who are not eligible for the cancer drug Herceptin as well as those with triple negative breast cancer. The current study correlates the extent of immune response with reduction in relapse. A priority in all forms of cancer immunotherapy today is in establishing means of identifying which patients are more likely to respond to treatment.

The current results add to prior studies both from the ongoing Phase II trial as well as a completed Phase I study of AE37 in patients with prostate cancer showing robust yet specific immunological responses together with almost negligible toxicity. The distinguishing feature of AE37 is its ability to specifically activate CD4+ T helper cells, which govern both the quality and magnitude of an immune response to a novel target. The correlation of a robust immune response with reduced relapse confirms the importance of this type of immunological activity in combating cancer.

Encouraging results from both the breast and prostate cancer trials of AE37 warrant further clinical development of AE37, both as mono- and/or combination therapy. The current study provides important biomarker information relevant to identifying those patients who may be expected to benefit most from AE37. Similarly, the information may help guide possible combination studies; i.e., using agents that may enable all patients to respond robustly to AE37 (e.g., checkpoint inhibitors).

On April 20, 2015 Medigene AG (MDG1, Frankfurt, Prime Standard) reported that early clinical data of its dendritic cell (DC) vaccines were presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Philadelphia, USA (Press release, MediGene, APR 20, 2015, View Source [SID:1234506589]). The clinical data were collected in an ongoing compassionate use program[1] conducted at the Department of Cellular Therapy at the Oslo University Hospital, Norway, under the responsibility of Prof. Gunnar Kvalheim. The poster presentation titled "A new generation of dendritic cells to improve cancer therapy shows prolonged progression free survival in patients with solid tumors" provides data from patients with various types of tumour which were included in this program.

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In summary, one lung cancer patient, one prostate cancer patient, four glioblastoma patients and three acute myeloid leukaemia (AML) patients have started treatment with dendritic cells so far. The new generation of dendritic cells characterized by superior in-vitro functionality when compared to commonly used dendritic cells could be produced from cells of all patients, regardless of the type of malignancy. The included patients suffering from solid tumours clearly showed a longer progression free survival than could be expected according to the stage of their disease, except for the patient with prostate cancer, who due to personal reasons prematurely dropped out of the program. The three AML patients which were included in this dendritic cell compassionate use program have been showing a promising course of disease, however these cases are still too early for evaluation.

Conclusion of this evaluation by Prof. Gunnar Kvalheim, Head of Department of Cellular Therapy, Oslo University Hospital: "Solid tumour patients suffering from advanced disease treated with these DC vaccines have a prolonged progression free survival, showing that this immunotherapeutic approach will be a promising alternative to current standard therapies."

More detailed information can be found in the abstract under the following link: View Source;sKey=eae2d342-dd5a-41ba-9eb4-63990d3122b8&cKey=1ff23671-9f76-44fd-891b-50b8fbfdd1b6&mKey=19573a54-ae8f-4e00-9c23-bd6d62268424

The Oslo University Hospital has an agreement with Medigene for use of Medigene`s new generation DC vaccines for their ongoing academic clinical studies.

Prof. Dolores J. Schendel, Chief Scientific Officer of Medigene AG: "These positive results encourage us in pursuing our DC vaccine development program for which we have recently started our own clinical AML trial, complementing the ongoing academic clinical studies."

About Medigene’s DC vaccines: The platform for the development of new generation antigen-tailored DC vaccines is the most advanced platform of the three highly innovative and complementary immunotherapy platforms of Medigene Immunotherapies. The DC vaccines are currently being evaluated in a company-sponsored clinical trial in acute myeloid leukaemia (AML) as well as in two ongoing clinical investigator-initiated trials: a clinical phase I/II trial in AML at the Ludwig-Maximilian University Hospital Großhadern, Munich, and a clinical phase II trial in prostate cancer at the Oslo University Hospital. Moreover, a compassionate use program is being conducted at the Department of Cellular Therapy at the Oslo University Hospital.

Medigene’s dendritic cell product platform allows the design of new generation dendritic cell vaccines. Dendritic cells can take up antigens efficiently, process them and present them on their surface in a form that can induce antigen-specific T cells to proliferate and mature. This way T cells can recognize and eliminate antigen-bearing tumour cells. Dendritic cells can also induce natural killer cells (NK cells) to become active and attack tumour cells. Scientists of Medigene Immunotherapies have developed new, fast and efficient methods for preparing autologous (patient-specific) mature dendritic cells which have relevant characteristics to activate both T cells and NK cells. The dendritic cells can be loaded with various tumour antigens to treat different types of cancer and are designed for treatment of minimal residual disease or use in combination therapies.

On April 17, 2015 Panther Biotechnology, Inc. ( OTC PINK : PBYA ), a biotechnology company specializing in the development of enhanced therapeutics for the treatment of neoplastic disorders reported that it has entered into an exclusive global license agreement with the University of Rochester (Press release, Panther Biotechnology, APR 17, 2015, View Source [SID1234517371]).

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Under the terms of the agreement, Panther has licensed from the University of Rochester, the rights to develop and commercialize a first in class new chemical entity with demonstrated powerful anti-leukemia activity. The licensed compound, called TDZD-8, is a small molecule engineered to kill leukemic stem cells. TDZD-8 has demonstrated broad and selective in vitro activity against many different types of leukemia. In addition, TDZD-8 has no significant toxicity in normal hematopoietic stem cells. The license is based on the pending US patent 12/374,002, pending EU patent 07810619.2, issued Australia patent 2007275686, and issued New Zealand patent 574619, all filed under "Thiadiazolidinone Derivatives."

"Leukemia is thought to arise from malignant stem cells that are relatively resistant to current chemotherapy and likely contribute to disease relapse and progression. Therefore, the identification of drugs that can efficiently eradicate leukemia stem cells is an important priority," stated Craig T. Jordan, PhD., the University of Rochester Medical Center leading inventor. "We believe that TDZD-8 uses a unique and previously unknown mechanism to rapidly target leukemia cells, including malignant stem and progenitor populations."

Studies of TDZD-8 were performed to determine the effects on different types of leukemia cells taken from patients (AML, bcCML, CLL and ALL), and on normal blood cells as well. All forms of leukemia cells were strongly inhibited and induced to die by TDZD-8, however, there was minimal effect on normal blood cells. Further, TDZD-8 was submitted for screening against the NCI60 panel and found to be selectively cytotoxic to leukemia cells and cells from related diseases. The compound does not greatly impact tumors derived from non-blood tissues.

TDZD-8 is a kinase inhibitor and induces oxidative stress, causing its striking ability to induce the leukemia cells to die after less than 2 hours of exposure to the drug.

"This license agreement represents an opportunity to augment our chemotherapeutics portfolio with drugs aimed at survival extension and low toxicity with a cutting edge, cancer stem cell targeting drug," stated Evan Levine, Chief Executive Officer of Panther. "As we continue advancing our programs, we look forward to moving TDZD-8 into the clinic to target cancer stem cells and complement our other drugs that target the bulk tumor." Mr. Levine added, "Panther has now established a robust pipeline and is continuing its acquisition strategy with the goal of adding more advanced clinical stage products."

"Even as targeted agents and immunotherapeutic approaches come of age, chemotherapy remains a staple of a large number of effective cancer treatment regimens — and will remain so for a long time. Improving chemotherapy by adding new compounds such as Numonafide and TRF-DOX (transferrin-doxorubicin conjugate) to the clinical toolbox will undoubtedly improve patient outcome," stated Jayesh Mehta MD, Professor of Medicine and Director of Hematopoietic Stem Cell Transplantation at the Northwestern University Feinberg School of Medicine. "With our new collaboration with the University of Rochester, Panther is now looking into the future and we are excited to complement our growing pipeline with TDZD-8, which is a state-of-the-art compound directed at the leukemic stem cell. This type of drug will eventually change the way we treat patients and improve response rates."