Uncategorized – Page 16790 – 1stOncology™: Cancer Intelligence Service

Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair.

Trabectedin (Yondelis, ecteinascidin-743, ET-743) is a marine-derived natural product approved for treatment of advanced soft tissue sarcoma and relapsed platinum-sensitive ovarian cancer. Lurbinectedin is a novel anticancer agent structurally related to trabectedin. Both ecteinascidins generate DNA double-strand breaks that are processed through homologous recombination repair (HRR), thereby rendering HRR-deficient cells particularly sensitive. We here characterize the DNA damage response (DDR) to trabectedin and lurbinectedin in HeLa cells. Our results show that both compounds activate the ATM/Chk2 (ataxia-telangiectasia mutated/checkpoint kinase 2) and ATR/Chk1 (ATM and RAD3-related/checkpoint kinase 1) pathways. Interestingly, pharmacological inhibition of Chk1/2, ATR or ATM is not accompanied by any significant improvement of the cytotoxic activity of the ecteinascidins while dual inhibition of ATM and ATR strongly potentiates it. Accordingly, concomitant inhibition of both ATR and ATM is an absolute requirement to efficiently block the formation of γ-H2AX, MDC1, BRCA1 and Rad51 foci following exposure to the ecteinascidins. These results are not restricted to HeLa cells, but are shared by cisplatin-sensitive and -resistant ovarian carcinoma cells. Together, our data identify ATR and ATM as central coordinators of the DDR to ecteinascidins and provide a mechanistic rationale for combining these compounds with ATR and ATM inhibitors.

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Medtronic Receives Expanded Indication From FDA for Pillcam(TM) Colon 2 Capsule

On March 31, 2016 Medtronic plc (NYSE: MDT) reported that the U.S. Food and Drug Administration (FDA) cleared PillCam(TM) COLON 2 capsule for an expanded indication for use (Press release, Medtronic, MAR 31, 2016, View Source;p=RssLanding&cat=news&id=2152086 [SID:1234510245]). The PillCam(TM) COLON 2 capsule is the only non-invasive diagnostic test that directly visualizes the colon for the evaluation of polyps in patients who are at major risks for colonoscopy or moderate sedation. The PillCam(TM) capsule- a vitamin-sized capsule endoscope that is taken orally – does not require sedation, anesthesia or radiation, which makes it a more convenient procedure than other invasive colon exams.

This expanded indication is for the detection of colon polyps in patients with evidence of gastrointestinal bleeding of lower gastrointestinal (Gl) origin. This applies only to patients with major risks for colonoscopy or moderate sedation, but who could tolerate colonoscopy and moderate sedation in the event a clinically significant colon abnormality was identified on capsule endoscopy.

Colon cancer is the third most commonly diagnosed cancer and second leading cause of cancer death in both men and women combined in the U.S. An estimated 136,000 people will be diagnosed with colorectal cancer each year, but when it is caught at a localized stage, the overall 5-year survival rate is 90%.[i]

According to Gastrointestinal Endoscopy, 14 million colonoscopiesare performed in the U.S. each year – of these, more than 3 million are performed for lower GI bleeding, and 600 thousand of those patients are at elevated risk for complications. [ii] [iii]
"The ability to offer PillCam COLON capsule to an expanded patient group represents a significant breakthrough in GI healthcare," said Douglas Rex, M.D., Distinguished Professor of Medicine and Chancellor’s Professor, Indiana University School of Medicine and Director of Endoscopy, IU Health University Hospital. "The new indication allows gastroenterologists to provide their at-risk patients with a non-invasive and radiation free alternative to traditional colonoscopy."

"We are committed to the early detection and treatment of chronic GI diseases and cancers. We are pleased with the FDA’s decision to clear this expanded indication for PillCam(TM) COLON capsule which will provide access to more patients who can benefit from this technology," said Vafa Jamali, president, Early Technologies business in the Medtronic Minimally Invasive Therapies Group.

PillCam(TM) COLON 2 capsule was previously cleared by the FDA for visualization of the colon and the detection of colon polyps in patients following an incomplete colonoscopy with adequate preparation, and a complete evaluation of the colon was not technically possible. The PillCam(TM) capsule technology may also limit the risk of complications that could occur from a standard colonoscopy, such as colon perforation, bleeding or cardio-pulmonary complications.

20-F – Annual and transition report of foreign private issuers [Sections 13 or 15(d)]

(Filing, Annual, Can-Fite BioPharma, 2015, MAR 31, 2016, View Source [SID:1234510271])

Cognitive Testing of an Electronic Version of the Faces Pain Scale-Revised with Pediatric and Adolescent Sickle Cell Patients.

Patient diaries and pain scales can capture the course and complications of pain managed at home in children. The Faces Pain Scale-Revised (FPS-R) is a validated scale showing reliability in children, but it has not been validated in children with sickle cell disease (SCD).
The purpose of this study was to evaluate comprehension and usability of an electronic modified version of the FPS-R among pediatric patients with SCD.
This was a cross-sectional, qualitative study involving in-person interviews with children/adolescents from the USA and their parents/legal guardians. Interviews involved cognitive debriefing and usability testing of the FPS-R.
In total, 22 children with SCD aged 4-17 years participated. Children aged 4-6 were generally unable to demonstrate clear understanding of the FPS-R and its response scale. Overall, children aged ≥7 years understood the instrument and could complete it on the electronic device, although children aged 7-8 often needed assistance from the parent. Children aged 9-17 years were able to read and complete the instrument independently. Most participants considered the electronic device easy to use.
The FPS-R was shown to be a comprehensible and usable pain measure for children aged 7-17 with SCD and to be beneficial for future clinical studies.

DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising anti-tumor efficacy with differentiation from T-DM1.

An anti-HER2 antibody drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new anti-tumor drug candidate, and its preclinical pharmacological profile was assessed.
In vitro and in vivo pharmacological activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys and the safety profiles in rats and cynomolgus monkeys were assessed.
DS-8201a exhibited a HER2 expression-dependent cell growth inhibitory activity and induced tumor regression with a single dosing at more than 1 mg/kg in a HER2-positive gastric cancer NCI-N87 model. Binding activity to HER2 and ADCC activity of DS-8201a were comparable to unconjugated anti-HER2 antibody. DS-8201a also showed an inhibitory activity to Akt phosphorylation. DS-8201a induced phosphorylation of Chk1 and Histone H2A.X, the markers of DNA damage. Pharmacokinetics and safety profiles of DS-8201a were favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys, supporting DS-8201a’s being well tolerated in humans. DS-8201a was effective in a T-DM1-insensitive PDX model with high HER2 expression. DS-8201a, but not T-DM1, demonstrated anti-tumor efficacy against several breast cancer PDX models with low HER2 expression.
DS-8201a exhibited a potent anti-tumor activity in a broad selection of HER2-positive models and favorable pharmacokinetics and safety profiles. The results demonstrate that DS-8201a will be a valuable therapy with a great potential to respond to T-DM1 insensitive HER2 positive cancers and low HER2-expressing cancers.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Category: Uncategorized

Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair.

Medtronic Receives Expanded Indication From FDA for Pillcam(TM) Colon 2 Capsule

20-F – Annual and transition report of foreign private issuers [Sections 13 or 15(d)]

Cognitive Testing of an Electronic Version of the Faces Pain Scale-Revised with Pediatric and Adolescent Sickle Cell Patients.

DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising anti-tumor efficacy with differentiation from T-DM1.