Panel Calls for More Research in Advanced Breast Ca

“The lack of options for advanced breast cancer has created a sense of urgency for high-quality research and clinical trials to address a multitude of unanswered questions, a guideline panel concluded.

“Though treatment advances have extended the duration of survival, advanced breast cancer remains almost uniformly fatal. Consequently, the principal goals have been to improve the length and quality of life for patients.

“Against that backdrop of modest progress and considerable futility, a panel representing the European School of Oncology (ESO) and the European Society of Medical Oncology (ESMO) developed the second international guidelines for management of advanced breast cancer (ABC2).

” ‘I don’t think that we generalize about individual patients,’ guideline co-chair Eric Winer, MD, of Dana-Farber Cancer Institute in Boston, told MedPage Today. ‘With each and every patient, we have to assess exactly what kind of breast cancer she has, where it has spread to, what other kinds of medical problems she has, and based on this info, give women — and occasionally men — a much better sense of their prognosis.’

“The guidelines were published simultaneously in Annals of Oncology and The Breast.

“In part, the lack of progress can be traced to the inherently slow pace of clinical development, said guideline co-chair Fatima Cardoso, MD, of the Champalimaud Cancer Center in Lisbon, Portugal. The traditional approach to clinical research has been to begin with patients who have metastatic breast cancer and then move the evaluation of promising therapies to earlier stages, effectively ending research in patients with advanced disease.

” ‘In one sense, this is correct because we need to provide the highest number of patients as early as possible with the new drugs,’ Cardoso said in a statement. ‘But if we do that all the time, we will leave the metastatic patients without any good knowledge of how to treat them.’ ”


Cancer Drug Discovery System is Broken, Global Summit Hears

“The global system for discovering new cancer drugs is ‘broken’, and failing to turn dramatic scientific advances into enough innovative, game-changing medicines, a world-leading UK expert has warned.

“Professor Paul Workman, Interim Chief Executive of The Institute of Cancer Research, London, told the World Oncology Forum that big leaps forward in cancer treatment were now possible – but only with major changes to the model for discovering and developing drugs.

“In his keynote lecture Professor Workman – one of the world’s leading experts in cancer drug discovery – said that concerted action was needed by governments, pharmaceutical companies, regulators and academic institutions to fix a system that was failing to take the risks needed to deliver exciting new treatments.

“Professor Workman told the summit in Lugano, Switzerland, that drugs were only available for 5% of the 500 known cancer drug targets – and that far more were needed to deliver the combination treatments that are essential to overcome the major problem of cancer evolution and drug resistance.

“The World Oncology Forum – only the second to have been organised – brings together 50 global leaders in cancer research and treatment in order to come up with policy recommendations designed to improve treatments across the world.

“Professor Workman said that the overall ‘ecosystem’ of pharmaceutical companies, academic institutions, government and regulators was far too risk averse, mostly tending to work in the same areas of research and producing ‘me too’ drugs, similar to others on the market, rather than genuinely new, innovative medicines.”


Navigating the Therapeutic Complexity of PI3K Pathway Inhibition in Melanoma

“Melanoma is entering into an era of combinatorial approaches to build upon recent clinical breakthroughs achieved by novel single-agent therapies. One of the leading targets to emerge from the growing understanding of the molecular pathogenesis, heterogeneity, and resistance mechanisms of melanomas is the phosphoinositide 3-kinase (PI3K)–AKT pathway. Multiple genetic and epigenetic aberrations that activate this pathway have been identified in melanomas de novo and in acquired resistance models. These developments have been paralleled by the establishment of models for preclinical testing and the availability of compounds that target various effectors in the pathway. Thus, in addition to having a strong rationale for targeting, the PI3K–AKT pathway presents an immediate clinical opportunity. However, the development of effective strategies against this pathway must overcome several key challenges, including optimizing patient selection, overcoming feedback loops, and pathway cross-talk that can mediate resistance. This review discusses the current understanding and ongoing research about the PI3K–AKT pathway in melanoma and emerging strategies to achieve clinical benefit in patients by targeting it.”


Cancer: Killing from the Inside

“Lysosomes are the main degradative compartment in cells, but they are also involved in cell-death pathways. Studies using existing drugs show that lysosomes are excellent pharmacological targets for selectively destroying cancer cells.”


Cancer: Killing from the Inside

“Lysosomes are the main degradative compartment in cells, but they are also involved in cell-death pathways. Studies using existing drugs show that lysosomes are excellent pharmacological targets for selectively destroying cancer cells.”


Cancer: Killing from the Inside

“Lysosomes are the main degradative compartment in cells, but they are also involved in cell-death pathways. Studies using existing drugs show that lysosomes are excellent pharmacological targets for selectively destroying cancer cells.”


Cancer Cell – Transformation-Associated Changes in Sphingolipid Metabolism Sensitize Cells to Lysosomal Cell Death Induced by Inhibitors of Acid Sphingomyelinase

“Lysosomal membrane permeabilization and subsequent cell death may prove useful in cancer treatment, provided that cancer cell lysosomes can be specifically targeted. Here, we identify acid sphingomyelinase (ASM) inhibition as a selective means to destabilize cancer cell lysosomes. Lysosome-destabilizing experimental anticancer agent siramesine inhibits ASM by interfering with the binding of ASM to its essential lysosomal cofactor, bis(monoacylglycero)phosphate. Like siramesine, several clinically relevant ASM inhibitors trigger cancer-specific lysosomal cell death, reduce tumor growth in vivo, and revert multidrug resistance. Their cancer selectivity is associated with transformation-associated reduction in ASM expression and subsequent failure to maintain sphingomyelin hydrolysis during drug exposure. Taken together, these data identify ASM as an attractive target for cancer therapy.”


Cancer Cell – Transformation-Associated Changes in Sphingolipid Metabolism Sensitize Cells to Lysosomal Cell Death Induced by Inhibitors of Acid Sphingomyelinase

“Lysosomal membrane permeabilization and subsequent cell death may prove useful in cancer treatment, provided that cancer cell lysosomes can be specifically targeted. Here, we identify acid sphingomyelinase (ASM) inhibition as a selective means to destabilize cancer cell lysosomes. Lysosome-destabilizing experimental anticancer agent siramesine inhibits ASM by interfering with the binding of ASM to its essential lysosomal cofactor, bis(monoacylglycero)phosphate. Like siramesine, several clinically relevant ASM inhibitors trigger cancer-specific lysosomal cell death, reduce tumor growth in vivo, and revert multidrug resistance. Their cancer selectivity is associated with transformation-associated reduction in ASM expression and subsequent failure to maintain sphingomyelin hydrolysis during drug exposure. Taken together, these data identify ASM as an attractive target for cancer therapy.”


Cancer Cell – Transformation-Associated Changes in Sphingolipid Metabolism Sensitize Cells to Lysosomal Cell Death Induced by Inhibitors of Acid Sphingomyelinase

“Lysosomal membrane permeabilization and subsequent cell death may prove useful in cancer treatment, provided that cancer cell lysosomes can be specifically targeted. Here, we identify acid sphingomyelinase (ASM) inhibition as a selective means to destabilize cancer cell lysosomes. Lysosome-destabilizing experimental anticancer agent siramesine inhibits ASM by interfering with the binding of ASM to its essential lysosomal cofactor, bis(monoacylglycero)phosphate. Like siramesine, several clinically relevant ASM inhibitors trigger cancer-specific lysosomal cell death, reduce tumor growth in vivo, and revert multidrug resistance. Their cancer selectivity is associated with transformation-associated reduction in ASM expression and subsequent failure to maintain sphingomyelin hydrolysis during drug exposure. Taken together, these data identify ASM as an attractive target for cancer therapy.”