OnApril 22, 2016 Provectus Biopharmaceuticals, Inc. (NYSE MKT: PVCT, www.pvct.com), a clinical-stage oncology and dermatology biopharmaceutical company ("Provectus" or "the Company"), reported that researchers from Moffitt Cancer Center in Tampa, Florida, presented a poster titled, "T cell Mediated Immunity After Combination Therapy with Intralesional PV-10 and Co-Inhibitory Blockade in a Melanoma Model," at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016, held at the Ernest N. Morial Convention Center in New Orleans, Louisiana (Press release, Provectus Pharmaceuticals, APR 22, 2016, https://www.pvct.com/pressrelease.html?article=20160422.1 [SID:1234511391]).

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In the poster, authors Amy M Weber, Hao Liu, Krithika Kodumudi, Amod A Sarnaik and Shari Pilon-Thomas state that "treatment with IL PV-10 and anti-PD-1 antibody results in a delay in tumor growth and enhanced T cell activation in the M05 tumor model." They also conclude that "the effect of combination therapy with IL PV-10 and PD-1 blockade is mediated by CD8+ T cells, and depletion of either CD4+ T cells or CD25+ Tregs enhances anti-tumor immunity in the M05 melanoma model." The abstract of the poster (number 4978) may be viewed at View Source;sKey=2923b796-8c3a-4376-8adb-7b669b666d8f&cKey=727ae663-75cd-4102-8a98-34de39d3a95f&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267.

Shari Pilon-Thomas, Ph.D., who leads the research team at Moffitt, noted, "Our results show that combining intralesional PV-10 with anti-PD-1 co-inhibitory blockade not only suppresses tumor growth vs. either agent alone but also yields marked increases in tumor-specific T cell activation against injected tumor."

Eric Wachter, Ph.D., Chief Technology Officer of Provectus, observed, "The nonclinical data reported by our collaborators at Moffitt reaffirm the crucial role T cells play in response to tumor ablation with intralesional PV-10, and further demonstrate the potential value of combining PV-10 with T cell directed checkpoint inhibition, such as the anti-PD-1 agent pembrolizumab. Intriguingly, these data also highlight possible strategies for augmenting this paradigm by harnessing additional targets in T cell signaling."

Provectus is currently enrolling patients in a phase 3 study of PV-10 as a single agent therapy for patients with locally advanced cutaneous melanoma (Clinical Trials ID NCT02288897) and in a phase 1b study of PV-10 in combination with the immune checkpoint inhibitor pembrolizumab in patients with metastatic melanoma (Clinical Trials ID NCT02557321).

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The mission of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) is to prevent and cure cancer through research, education, communication, and collaboration. Through its programs and services, the AACR (Free AACR Whitepaper) fosters research in cancer and related biomedical science; accelerates the dissemination of new research findings among scientists and others dedicated to the conquest of cancer; promotes science education and training; and advances the understanding of cancer etiology, prevention, diagnosis, and treatment throughout the world.

The AACR (Free AACR Whitepaper) is the oldest and largest scientific organization in the world focused on every aspect of high-quality, innovative cancer research. Its reputation for scientific breadth and excellence attract the premier researchers in the field. The programs and services of the AACR (Free AACR Whitepaper) foster the exchange of knowledge and new ideas among scientists dedicated to cancer research, provide training opportunities for the next generation of cancer researchers, and increase public understanding of cancer.

The high rate of failure of new agents in oncology clinical trials indicates a weak understanding of the complexity of human cancer. Recent understanding of the mechanisms underlying castration resistance in prostate cancer led to the development of new agents targeting the androgen receptor pathway; however, their effectiveness is limited. Hence, there is a need for experimental systems that are able to better reproduce the biological diversity of prostate cancer in preclinical settings. In this study, we established a unique patient-derived xenograft (PDX) model to identify biomarkers for treatment efficacy and resistance and better understand prostate cancer biology.
A prostate cancer tissue sample from a Japanese patient was transplanted subcutaneously into male, severe combined immune-deficient (SCID) mice and this PDX mouse model was named KUCaP3. Sequential tumor volume changes were observed before and after castration. Androgen receptor (AR), prostate-specific antigen (PSA), and other molecular markers were examined immunohistochemically. Sequence analysis of AR was also performed to detect mutations. Proteomic analysis of cyst fluid and sera samples of KUCaP3 mice were analyzed by mass spectrometry (MS).
KUCaP3 cell line, derived from human tissue, was successfully and serially passaged in vivo with approximately 60% take rate. KUCaP3 exhibited cyst formation, showed androgen-dependent growth initially, and developed castration-resistant growth several months after castration of the mice. Immunohistochemical analysis showed that KUCaP3 was positive for AR, PSA, CK18, and α-methyl acyl-coenzyme A racemase, but negative for CK5/6 and ERG. The AR gene in KUCaP3 cells contained a substitution from CAT (histidine) to TAT (tyrosine) at the nucleotide positions corresponding to codon 875 (H875Y) in the ligand-binding domain. Chemiluminescent immunoassay revealed higher levels of PSA in cystic fluid and the serum of KUCaP3-bearing mice. MS analysis detected 23 proteins of human origin in cystic fluids of KUCaP3.
We developed KUCaP3, an androgen-dependent PDX model with cyst formation. Several proteins including PSA were detected in the cystic fluid and sera of tumor-bearing mice. This original PDX model has the potential to be used as a clinically relevant model to evaluate molecular markers for prostate cancer diagnosis and treatment. Prostate © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.

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While much progress has been made in the treatment of breast cancer, cardiac complications resulting from therapy remain a significant concern. Both anthracyclines and novel targeted agents can inflict cardiac damage. The present study aimed to evaluate the difference between what it is currently done and what standards of care should be used to minimizing and managing cardiac toxicity in breast cancer survivors.
A two-round multicenter Delphi study was carried out. The panel consisted of 100 oncologists who were asked to define the elected therapies for breast cancer patients, the clinical definition and patterns of cancer drug-derived cardiac toxicity, and those protocols focused on early detection and monitoring of cardiovascular outcomes.
Experts agreed a more recent definition of cardiotoxicity. Around 38 % of patients with early-stage disease, and 51.3 % cases with advanced metastatic breast cancer had preexisting risk factors for cardiotoxicity. Among risk factors, cumulative dose of anthracycline ≥450 mg/m(2) and its combination with other anticancer drugs, and a preexisting cardiovascular disease were considered the best predictors of cardiotoxicity. Echocardiography and radionuclide ventriculography have been the proposed methods for monitoring changes in cardiac structure and function. Breast cancer is generally treated with anthracyclines (80 %), so that the panel strongly stated about the need to plan a strategy to managing cardiotoxicity. A decline of left ventricular ejection fraction (LVEF) >10 %, to an LVEF value <53 % was suggested as a criterion for changing the dose schedule of anthracyclines, or suspending the treatment of chemotherapy plus trastuzumab until the normalization of the left ventricular function. The use of liposomal anthracyclines was strongly suggested as a treatment option for breast cancer patients.
The present report is the first to produce a set of statements on the prevention, evaluation and monitoring of chemotherapy-induced cardiac toxicity in breast cancer patients.

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Lipid biomarkers, such as HDL-cholesterol concentrations, have been shown to have positive, inverse, and null associations with total, breast, and colorectal cancer risks. Studies of novel lipid biomarkers, such as apolipoprotein A-I (apo A-I) and apolipoprotein B-100 (apo B-100), and cancer risk have been sparse, to our knowledge.
We evaluated the prospective association of total, breast, colorectal, and lung cancers and cancer mortality with circulating lipid biomarkers in 15,602 female health professionals in the Women’s Health Study (aged ≥45 y, free of cardiovascular disease and cancer, and without hormone replacement therapy or lipid-lowering medications at baseline).
Cox regression models estimated HRs of cancer endpoints (19 y median follow-up) across quartiles 1 (reference) to 4 of each lipid biomarker after adjustment for cancer risk factors.
Confirmed cases included 2163 incident cancer cases (864 breast, 198 colorectal, and 190 lung cancers) and 647 cancer deaths. Total cancer risk was significantly lower in the highest quartile of apo A-I (adjusted HR: 0.79; 95% CI: 0.70, 0.90;P-trend = 0.0008) and HDL cholesterol (HR: 0.85; 95% CI: 0.75, 0.97;P-trend = 0.01). For site-specific cancers, significant associations included colorectal cancer risk with HDL cholesterol (HR: 0.63; 95% CI; 0.41, 0.98;P-trend = 0.03), triglycerides (HR: 1.86; 95% CI: 1.17, 2.97;P-trend = 0.02), and apo B-100 (HR: 1.60; 95% CI: 1.03, 2.49;P-trend = 0.006) and lung cancer risk with HDL cholesterol (HR: 0.59; 95% CI: 0.38, 0.93;P-trend = 0.01). LDL cholesterol was not significantly associated with risk of total cancer or any site-specific cancers. In time-dependent models that were adjusted for the use of a lipid-lowering medication after baseline, these associations remained.
Lipids were associated with total, lung, and colorectal cancer risks in women. Lifestyle interventions for heart-disease prevention, which reduce apo B-100 or raise HDL cholesterol, may be associated with reduced cancer risk. The Women’s Health Study was registered atclinicaltrials.govasNCT00000479.
© 2016 American Society for Nutrition.

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On April 22, 2016 Kancera reports that ROR inhibitors have been tested against human triple negative breast cancer transferred to zebrafish (Press release, Kancera, APR 22, 2016, View Source;releaseID=1138564 [SID:1234511316]). The experiments showed that Kancera’s small molecule ROR inhibitors are able to both reduce tumor size and metastases (spread) of this aggressive tumor form. Further, Kancera reports that the company´s PFKFB3 inhibitors are active in the same model of triple negative breast cancer and that a patent application has been filed covering the discovery that PFKFB3 inhibitors enhance the effect of radiation treatment.

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Kancera has previously reported that a new generation of ROR inhibitors (e.g. the compound KAN0440550) have been developed and these show a high level of efficacy and selectivity against cancer cells compared with healthy cells at the same time as they reach a concentration in the blood after oral administration that is expected to be sufficient to achieve efficacy against several cancers such as lymphoma and solid tumors. Kancera has now examined the effect of a representative of this new generation of ROR inhibitors against solid tumor in a disease model based on a human triple negative breast cancer* implanted and studied in zebrafish. The results show that a three day treatment with a ROR inhibitor results in both reduced tumor growth and reduced metastasis (spread). The study also shows that KAN0440550 is well tolerated at the effective concentration of the compound. KAN0440550 and related ROR inhibitors are now being tested against solid cancers and lymphomas in preclinical disease models for the selection of a candidate drug complementary to KAN0439834 which is a compound that is more suited for effect against leukemia.

Kancera´s PFKFB3 inhibitor (KAN0438757) has previously been shown to be effective against the same form of breast cancer model as the ROR inhibitors above *. An additional zebrafish study verified the effect of Kancera’s PFKFB3 inhibitor in monotherapy (treatment with substance without combining it with another therapy). Kancera’s PFKFB3 inhibitor was well tolerated at the active concentration of the compound. Kancera has previously reported a discovery, made together with Professor Thomas Helleday’s research team at the Karolinska Institute, that treatment with Kancera´sPFKFB3 inhibitor enhances the effect of radiation on cancer cells in laboratory studies. This discovery has now been claimed in the United States by complementing the company’s earlier patent application which protects the PFKFB3-inhibiting compounds. Kancera is the owner also of this new patent application.

* Triple negative since three drug targets are missing due to genetic changes which makes it especially difficult to treat.

About the ROR project
ROR is a family of receptors, ROR1 and ROR2. The ROR receptors mediate signals for growth and survival. Originally ROR was linked to fetal development, but it is now known that they also contribute to cancer cell development and proliferation. Professor Håkan Mellstedt, Kancera´s co-founder and professor at the Karolinska Institute, and his colleagues have shown that Kancera´s ROR inhibitors have the ability to kill cells from tumors in pancreas and leukemia cells. Professor Mellstedt and his colleagues as well as independent researchers have shown that ROR is also active as a target in prostate, breast, skin and lung cancer.

Because ROR primarily generates a survival and growth signal to tumor cells but is inactive in healthy cells in adults, there are good prospects that a drug directed against ROR hit the tumor much harder than the surrounding healthy cells. Kancera and Professor Mellstedt have shown that inhibition of ROR leads to that cancer cells eliminate themselves by cellular suicide. Against this background, there are reasons to anticipate that a ROR-targeted drug is both safer and more effective than several chemotherapies currently used to treat cancer.

About the PFKFB3 project
By blocking mechanisms which enable the cancer cells to adapt to periods of oxygen deprivation, possibilities open for new treatment strategies. Kancera’s project is based on a specific inhibition of the enzyme PFKFB3 resulting in a decreased metabolism in cancer cells, and decreased cell growth. In addition, research shows that PFKFB3 is involved in the regulation of both angiogenesis and division of cells, two critical processes that contribute to tumor growth. PFKFB3 is more common in oxygen-deficient tumor tissue compared to healthy tissue, which makes a targeted effect therapy with fewer side effects than traditional chemotherapy possible. Inhibition of PFKFB3 is expected to starve and weaken the tumor cells by reducing their glycolysis and cell division. This is a way to overcome the current problems of tumor resistance to radiation and chemotherapy. Kancera’s PFKFB3 inhibitors have also been shown to prevent DNA repair in cancer cells following e.g. radiation treatment.