Hedgehog pathway as a drug target: Smoothened inhibitors in development

Emerging laboratory and clinical investigations demonstrate that Hedgehog signaling (Hh) represents a novel therapeutic target in various human cancers. This conserved signaling pathway precisely regulates self-renewal and terminal differentiation in embryonic development, but is typically silenced in adult tissues, with reactivation usually only during tissue repair. Aberrant Hh pathway signaling has been implicated in the pathogenesis, self-renewal, and chemotherapy resistance of a growing number of solid and hematologic malignancies. Major components of the Hh pathway include the Hh ligands (Sonic, Desert, and Indian), the transmembrane receptor Patched, the signal transducer Smoothened (Smo), and transcription factors Gli1–3 which regulate the transcription of Hh target genes. Mutations in Hh pathway genes, increased Hh signaling in tumor stroma, and Hh overexpression in self-renewing cells (cancer stem cells) have been described, and these different modes of Hh signaling have implications for the design of Hh pathway inhibitors and their integration into conventional treatment regimens. Discovery of a naturally-occurring Smo inhibitor, cyclopamine, and the identification of Hh pathway mutations and over expression in cancer cells prompted the development of several cyclopamine derivatives. Encouraging laboratory and in vivo data has resulted in Phase I and II clinical trials of Smo inhibitors. In this review, we will discuss the current understanding of Hh pathway signaling in malignancy and Smo antagonists in development. Recent data with these agents shows that they are well-tolerated and may be effective for subsets of patients. Challenges remain for appropriate patient selection and the optimal combination and sequence of these targeted therapies into current treatment paradigms

The important role of intensive induction chemotherapy in the treatment of acute myeloid leukemia.

Introduction: Intensive induction chemotherapy followed by post-remission consolidation and/or allogeneic hematopoietic transplantation has been a standard-of-care therapy for acute myeloid leukemia (AML) for decades. In recent years, a plethora of new agents have been approved for AML treatment, dramatically changing the AML treatment landscape.Areas covered: This review provides an overview of the current role of intensive chemotherapy in the changing AML treatment landscape. PubMed-indexed publications (through 2020) and abstracts presented at major national and international conferences were reviewed for inclusion.Expert opinion: While intensive chemotherapy is standard-of-care therapy for younger patients with AML, older patients were historically viewed as universally ineligible for intensive chemotherapy; however, several studies suggest many older patients benefit from intensive chemotherapy with a curative intent, and a more holistic approach to determining eligibility for intensive treatment is recommended. Intensive strategies have also been expanded to include novel chemotherapy designs and chemotherapy in combination with targeted agents for patients with certain disease characteristics, which may permit more personalized treatment decisions. Intensive chemotherapy continues to play a pivotal role for the management of many AML patients and can offer the best chance of long-term remission, especially when followed by transplantation

Cultural differences in intimacy: The influence of gender-role ideology and individualism-collectivism

Two studies examined emotional intimacy in European Canadian and Chinese Canadian dating relationships. Cultural differences in gender-role ideology and individualism–collectivism were hypothesized to differentially contribute to selfdisclosure and responsiveness, and in turn, intimacy. Study 1 revealed that Chinese Canadians’ lower intimacy relative to European Canadians was mediated by their greater gender-role traditionalism but not by their individualism or collectivism. Study 2 further linked greater gender-role traditionalism to lower self-disclosure, and in turn, lower intimacy. Results also revealed that Chinese Canadians’ lower intimacy mediated their lower relationship satisfaction and higher rate of relationship termination in Study 1, but that Chinese Canadians were not any more likely to terminate their relationships in Study 2

Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML

BACKGROUND: CPX-351 (United States: Vyxeos METHODS: Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses. RESULTS: The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology. CONCLUSIONS: This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 ( https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete