An Overview of the Changing Landscape of Treatment for Advanced Melanoma.

Abstract

PMID:

28052356

DOI:

10.1002/phar.1895

Melanoma-the deadliest form of skin cancer-leads to thousands of deaths each year. Although melanoma is less common than basal cell and squamous cell skin cancers, melanoma is more dangerous because it is more likely to spread to other parts of the body, such as lymph nodes, if not diagnosed and treated early. Data from the National Cancer Institute indicate a steady rise in new cases of melanoma and, unfortunately, a steady rate in the number of deaths through 2013. Ninety percent of melanomas are linked to inadequate sun protection from ultraviolet rays or the tanning habits of young adults.

Over the past 5 years, however, there have been a variety of new pharmacologic treatments for advanced melanoma including immunotherapy, targeted agents (BRAF and MEK inhibitors), and oncolytic viral therapy. In this article, we review the current literature on the treatment of melanoma, with a focus on emerging therapies.

CA125 as a predictive marker for optimal interval debulking surgery in advanced ovarian cancer

J Clin Oncol.2011 May 20;29(15_suppl):e15543.

Abstract

e15543 Background: Neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) is an accepted treatment for patients with advanced ovarian cancer. It is unclear, however, whether achieving optimal IDS can be predicted by preoperative analysis using imaging (CT and MRI) or by measuring cancer antigen (CA) 125 levels. The aim of the present study was to assess whether CA125 values can be used to identify patients who are candidates for optimal IDS following NAC for advanced ovarian cancer.

METHODS:

Eighty-one women diagnosed with ovarian cancer (6 FIGO IIIA and 75 IIIC) between 1995 and 2010, with serum CA125 levels greater than 40 IU/mL prior to NAC that underwent NAC followed by IDS, were retrospectively evaluated. After each NAC, CA 125 levels were measured and CA125 regression rates ([pre first NAC CA125 - pre each NAC CA125]/pre first NAC CA125) were calculated. Optimal IDS was defined as the largest volume of residual disease less than 1 cm in the maximal dimension. The ability of CA125 values and patient and disease characteristics to predict optimal IDS was determined by univariate and multivariate analyses.

RESULTS:

On univariate analysis, CA125 regression rates from pre first NAC to pre second NAC and from pre first NAC to pre third NAC, and CA125 levels before IDS were statistically significant (p less than 0.01). On multivariate analysis, CA125 level before IDS was an independent predictor of optimal IDS (p less than 0.01). The CA125 level cut-off point before IDS for optimal IDS calculated using a receiver operating characteristic curve was 9 IU/mL.

CONCLUSIONS:

In this retrospective study, a pre-IDS CA125 level of 9 IU/mL or less predicted optimal IDS.

 

 

How Precisely Can Prostate Cancer Be Managed?

Abstract

Progress has been made in applying genetic information to disease management in the postgenomic era, and precision medicine is emerging in prostate cancer management. The prostate health index, the 4-kallikrein (4K) score, and the PCA3, TMPRSS2- ERG, and Prostarix tests have potential for refining prostate cancer screening in conjunction with traditional prostate-specific antigen testing.
 
The Confirm MDx and PCA3 tests have shown promise in identifying men who need be rebiopsied after a primary negative biopsy. Oncotype DX, Prolaris, the biopsy-based Decipher prostate cancer test, and ProMark may improve predictive risk stratification in addition to the traditional Gleason score and tumor stage.

Decipher and Prolaris may predict biochemical recurrence and metastasis after radical prostatectomy and possibly help identify patients who need adjuvant therapy. Androgen receptor splice variant 7 appears effective in guiding the selection of second hormonal manipulation with abiraterone or enzalutamide versus chemotherapy when treating metastatic castration-resistant prostate cancer.

Int Neurourol J. 2016 Nov;20(Suppl 2):S120-130. Epub 2016 Nov 22

Targeted therapy for head and neck squamous cell carcinoma using the novel SMAC-mimetic birinapant

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the most prevalent cancer affecting the upper aerodigestive tract, with an annual incidence of 600,000 patients and a five year survival of approximately 60% worldwide. Molecular mechanisms driving the development of HNSCC have recently begun to be discovered, with The Cancer Genome Atlas (TCGA) uncovering the genomic landscape of 279 cases of HNSCC. Alterations in cell death pathways were commonly found in the TCGA analysis, with ∼30% of samples harboring 11q13/22 amplifications and overexpression of genes encoding for Fas-associated death domain (FADD) and/or cellular Inhibitor of Apoptosis Proteins 1/2 (cIAP1/2). While overexpression of cIAP1 has been implicated in resistance to cytotoxic therapies, the role of FADD amplification as a target for therapy and in mechanisms of cell death is not well understood. Birinapant is a novel second mitochondria-derived activator of caspases (SMAC)-mimetic that targets and promotes degradation of cIAPs. Its clinical efficacy is currently being investigated in phase II trials of patients with ovarian cancer and leukemia. However, its preclinical and clinical efficacies have not been tested in HNSCC and genomic markers of sensitivity remain to be defined. Here we hypothesized that overexpression of FADD and cIAP1/2 could modulate birinapant sensitivity in HNSCC. To test this hypothesis, we have treated a panel of 11 HPV(-) and 8 HPV(+) HNSCC cell lines with birinapant alone and in combination with death agonists TNFα or TRAIL. UMSCC-46, an HPV(-) cell line which possesses high FADD expression, was the only cell line to reach half maximal inhibitory concentration (IC₅₀) 72 hours post treatment with birinapant alone (IC₅₀ = 10.7 nM); however, 8 of 11 HPV(-) cell lines and all 8 HPV(+) cell lines attained an IC₅₀ (range: 0.1 - 794 nM) when treated with birinapant in combination with either TNFα or TRAIL. We further demonstrated that forced FADD overexpression in a previously resistant cell line (UMSCC-38) led to sensitization when treated with birinapant and TNFα. In vivo, two FADD/cIAP1 overexpressing murine xenograft models of HNSCC, UMSCC-46 and UMSCC-11B, were treated with birinapant at 15 mg/kg or 30 mg/kg every 3 days for a total of 10 treatments. The single modality regimen led to tumor growth inhibition and prolonged host survival. Additionally, combination treatment with birinapant 15 mg/kg and radiation 2Gy/day M-F for 2 weeks synergistically induced TNFα and led to a cure of animals bearing UMSCC-46 xenografts. Mechanistically, birinapant enhanced degradation of cIAP1 and modulated caspase apoptotic or MLKL necroptotic cell death markers in vitro and in vivo.

These results suggest that patients harboring genomic alterations in FADD and/or cIAP overexpression may be candidates for treatment with birinapant and radiation.

DOI: 10.1158/1538-7445.AM2016-3821 Published 15 July 2016

A NOVEL BREAKTHROUGH FOR ULTRASENSITIVE DETECTION OF RARE CANCER CELLS FROM EARLY BREAST CANCER PATIENTS

 

 

By: Wooyoung Hong, Sooyeon Lee, Hee Jin Chang, Eun Sook Lee, Youngnam Cho

Circulating tumor cells (CTCs) are recognized as promising biomarkers for diagnosis and indication of the prognosis of several epithelial cancers. However, at present, CTC monitoring is available only for advanced-stage patients rather than for those at an early stage of cancer. This is because of the extraordinary rarity of CTCs and the limited sensitivity of current methods. Herein, we report the development of multifunctional magnetic nanowires for the efficient isolation and detection of CTCs from the blood of patients, especially those with non-metastatic early-stage cancer. The nanowires, which are equipped with a high density of magnetic nanoparticles and five different types of antibodies (Ab mixture_mPpyNWs), offer a significant improvement in cell-isolation efficiency, even from very small amounts of blood (250 μL-1 mL). Notably, CTCs were isolated and identified in 29 out of 29 patients (100%) with non-metastatic early breast cancer, indicating that this procedure allowed detection of CTCs with greater accuracy, sensitivity, and specificity. In addition, we demonstrated in situ "naked eye" identification of the captured cancer cells via a simple colorimetric immunoassay.

Our results show that antibody-functionalized magnetic nanowires offer great potential for a broad range of practical clinical applications, including early detection, diagnosis, and treatment of cancer.

Affiliation

Molecular Imaging & Therapy Branch, National Cancer Center, 111 Jungbalsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do 410-769, South Korea. 

GI-6301 Is GlobeImmune's Third Oncology Tarmogen(R) Product to Begin Human Clinical Trials

LOUISVILLE, CO,   (MARKETWIRE via COMTEX) -- GlobeImmune, Inc. today announced the initiation of a Phase 1 clinical trial to be conducted at the National Cancer Institute (NCI) to investigate the safety and tolerability of GI-6301, a new Tarmogen product, for patients with metastatic cancers containing brachyury protein. Brachyury is over-expressed in a variety of important tumor types including breast, colon, lung and prostate cancers.

"Targeting the metastatic evolution of cancer is a unique application of our Tarmogen platform and for immunotherapy in general," said Timothy C. Rodell, M.D., President and CEO of GlobeImmune. "This trial potentially expands the utility of our Tarmogen platform that has already shown promise in patients with tumors expressing CEA and mutated Ras. We look forward to working with our NCI colleagues to successfully advance GI-6301 through the clinic."

The GI-6301 Tarmogen was jointly developed by GlobeImmune and NCI under a Collaborative Research and Development Agreement (CRADA). Preclinical studies supporting the filing of the IND were conducted at the Laboratory of Tumor Immunology and Biology (LTIB) at NCI led by Drs. Claudia Palena and Jeffrey Schlom. The single-center Phase 1 study will be funded by the NCI. The GI-6301-01 study is an open-label, dose-cohort escalation trial in patients with metastatic cancers with a high incidence of brachyury expression. The primary endpoint of the study is the safety and tolerability of escalating doses of GI-6301 given as a single agent. Secondary endpoints include levels of brachyury-specific T cells, reduction in brachyury serum markers and circulating tumor cells and evidence of clinical benefit. James L. Gulley, M.D., Ph.D., F.A.C.P., Director of the Clinical Trials Group, LTIB, will be the Principal Investigator for the study.

About the GI-6301 Tarmogen The GI-6301 Tarmogen consists of whole, heat-killed, recombinant S. cerevisiae yeast genetically modified to express high levels of brachyury protein. Brachyury is over-expressed in cancer cells compared with normal tissue and is believed to play a significant role in the progression of cancer from a localized to metastatic disease (the epithelial-to-mesenchymal transition, or EMT). Targeting brachyury using the GI-6301 Tarmogen is intended to arrest progression of disease by eliminating the subset of tumor cells that acquire drug resistance and the ability to migrate and invade distant tissues.

About GlobeImmune GlobeImmune is developing a new class of immunotherapy products called Tarmogens(R) that are designed to elicit a targeted T cell immune response to eliminate diseased cells. The immune system plays a critical role in controlling chronic infection and cancer. The Tarmogen platform is designed to reconstitute an appropriate immune response in patients to fight their disease. To date, Tarmogen products have been well tolerated in multiple disease indications and are efficient and scalable to manufacture. GlobeImmune has raised over $160 million to date in support of its programs. In July 2008, GlobeImmune signed a CRADA with NCI and the National Institutes of Health to jointly develop multiple product candidates intended to treat a variety of cancers. In May 2009, the Company announced a global partnership with Celgene focused on the discovery, development and commercialization of multiple product candidates for the treatment of cancer. In October 2011, the Company signed an exclusive research collaboration and license with Gilead to develop Tarmogens for the treatment of chronic hepatitis B (HBV) infection. For additional information, please visit the Company's website at www.globeimmune.com .

SOURCE: GlobeImmune, Inc.

Copyright 2012 Marketwire, Inc., All rights reserved

β2-Microglobulin Induces Epithelial to Mesenchymal Transition and Confers Cancer Lethality and Bone Metastasis in Human Cancer Cells

Bone metastasis is one of the predominant causes of cancer lethality. This study demonstrates for the first time how β2-microglobulin (β2-M) supports lethal metastasis in vivo in human prostate, breast, lung, and renal cancer cells. β2-M mediates this process by activating epithelial to mesenchymal transition (EMT) to promote lethal bone and soft tissue metastases in host mice. β2-M interacts with its receptor, hemochromatosis (HFE) protein, to modulate iron responsive pathways in cancer cells. Inhibition of either β2-M or HFE results in reversion of EMT. These results demonstrate the role of β2-M in cancer metastasis and lethality. Thus, β2-M and its downstream signaling pathways are promising prognostic markers of cancer metastases and novel therapeutic targets for cancer therapy. Cancer Res; 71(7); 2600–10. ©2011 AACR