Science Current Events | Science News | Brightsurf.com
 

Targeting protein homeostasis holds potential to treat solid tumors and blood cancers

December 04, 2015

The success of proteasome inhibitors such as VELCADE® (bortezomib) and Kyprolis® (carfilzomib) for the treatment of multiple myeloma has shown that protein homeostasis, which is how cells maintain a balance of protein synthesis and degradation, is a valid pathway for developing drugs to treat cancer. However, attacking the proteasome in solid tumors has not worked to date. New research published in the journals Cancer Cell and the Journal of Medicinal Chemistry highlights a novel approach to target protein homeostasis by inhibiting the protein p97 in both solid tumors and blood cancers. Preclinical data to be presented at the 57th ASH Annual Meeting & Exposition show specifically that targeting p97 induces disease regression in the blood cancer acute myeloid leukemia (AML).

Cancer cells often produce an overabundance of proteins, particularly misfolded proteins that are toxic to cells. Therefore, cancer cells rely upon the ubiquitin proteasome system (UPS), which is responsible in both healthy and tumor cells for eliminating surplus, misfolded and mutant proteins. The hyper-active UPS in tumor cells is critical for their survival. Without it, toxic proteins accumulate, and the tumor cells die.

p97 is a key mediator of several protein homeostasis processes. Among them, p97 mediates the extraction of cellular proteins destined for destruction by the UPS from organelles, chromatin and protein complexes. Scientists from Cleave Biosciences published in the Journal of Medicinal Chemistry the discovery and optimization of an orally bioavailable small molecule called CB-5083 that inhibits p97. In the paper published in Cancer Cell, the same researchers demonstrated that CB-5083 had antitumor activity in cancer cell lines and in various mouse tumor models, indicating its potential as a drug candidate.

"Researchers over the years have identified multiple inhibitors of p97, but until now those compounds have not successfully inhibited tumor growth in vivo," said Mark Rolfe, Ph.D., senior author on the paper and President and Chief Scientific Officer at Cleave Biosciences. "If we can successfully translate this to treat both solid tumors and blood cancers, we could have a very powerful strategy for treating patients with these life-threatening diseases."

CB-5083 has the potential to provide a completely new way to combat solid tumors such as colon, lung or breast cancer, as well as a number of different blood cancers. Despite the success of the proteasome inhibitors in treating multiple myeloma, the majority of other blood cancers are not responsive to such agents. AML, the most common acute leukemia in adults, is an aggressive disease with very poor outcomes -- only a quarter of patients survive five years. However, the treatment paradigm has remained relatively unchanged for over 40 years. Targeting protein homeostasis with CB-5083 has the potential to achieve clinical benefit in patients with AML that historically have had few options.

In data generated from a collaboration between scientists at Cleave Biosciences, the University of Southern California, the University of Texas, San Antonio, and the Cleveland Clinic that will be presented at ASH, CB-5083 demonstrated its potential in both established AML cell lines as well as primary AML cells. Treatment with CB-5083 in seven unique AML cell lines and 10 specimens of AML cells derived directly from patients demonstrated reduced cell line survival and increased cell death. In addition, CB-5083 was highly active in three different AML cell lines that are resistant to conventional AML treatments. In vivo, treatment with CB-5083 in two different mouse models was well tolerated and induced disease regression.

"It is important to note that in AML, both established cell lines as well as cells that came directly from patients, also known as primary cells, showed similar sensitivity to CB-5083," noted Dr. Rolfe. "Typically, primary cells show reduced sensitivity to both conventional and experimental drugs in AML, indicating that CB-5083 could be a powerful tool against AML, especially in patients who have relapsed or refractory disease."

###

Cleave Biosciences is studying CB-5083 in a Phase 1 trial in patients with advanced solid tumors with no available standard of care. Additionally, CB-5083 has been granted Orphan Drug Designation by the U.S. Food and Drug Administration for the treatment of multiple myeloma.

About Cleave Biosciences

Biopharmaceutical company Cleave Biosciences is a pioneer in the discovery and development of drugs that target protein homeostasis systems and have the potential to transform the treatment of people with difficult to treat solid tumors and hematologic malignancies. The company is privately held and located in Burlingame, California. For additional information, visit http://www.cleavebio.com.

Publication Citations

Zhou, HJ, et al. 'Discovery of a First-in-Class, Potent, Selective and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)'. J. Med. Chem. DOI/10.1021/acs.jmedchem.5b01346

Anderson, DJ, et al. 'Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis'. Cancer Cell. DOI 10.1016/j.ccell.2015.10.002.

Nawrocki ST, et al. 'Activation of the Unfolded Protein Response with the First-in-Class P97 Inhibitor CB-5083 Induces Stable Disease Regression and Overcomes Ara-C Resistance in AML' ASH Annual Meeting (2015) Session: 616, Abstract 1350

Canale Communications


Related Homeostasis Current Events and Homeostasis News Articles


New study surveys genetic changes linked with Parkinson's disease
After Alzheimer's, Parkinson's disease (PD) is the leading neurodegenerative disorder, affecting close to a million Americans, with 50,000 new cases diagnosed every year. A progressive disorder of the nervous system affecting movement, PD typically strikes adults in mid-life.

Enzyme pair play crucial role in maintaining balance of cellular processes
Researchers at St. Jude Children's Research Hospital have uncovered how two enzymes, ULK1 and ULK2, which are best known for their role in the degradation and recycling of proteins, control the trafficking of specific proteins.

How depression and antidepressant drugs work
New research demonstrates the effectiveness of ketamine to treat depression in a mouse model of the disease and brings together two hypotheses for the cause of depression.

New insights into human rare disorders with dogs
Professor Hannes Lohi's research group at the University of Helsinki has discovered three novel canine genes for Caffey, Raine and van den Ende-Gupta syndromes.

Research findings reveal potential to reverse cancer-related nerve pain
A study providing new information about neuropathic pain afflicting some 90 percent of cancer patients who have had nerve damage caused by tumors, surgery, chemotherapy or radiation indicates gene therapy as a possible treatment.

Scientists reveal endocardial origin of liver vasculature
On March 29, Nature Genetics published a research article entitled "Genetic lineage tracing identifies endocardial origin of liver vasculature", from Prof. ZHOU Bin's lab at the Institute for Nutritional Sciences (INS), Shanghai Institutes for Biological Sciences, CAS.

Sleep suppresses brain rebalancing
Why humans and other animals sleep is one of the remaining deep mysteries of physiology. One prominent theory in neuroscience is that sleep is when the brain replays memories "offline" to better encode them ("memory consolidation").

PERK-opathies: Stress mechanism underlying neurodegeneration
A major challenge in the field of neurodegeneration is the unclear understanding of neuronal dysfunction. Elucidation of these patho-mechanisms could result in the identification of novel therapeutic targets.

Better survival of implanted cells improves healing of bone fractures
To treat a complicated, non-healing bone defect, surgeons often use an implant with living cells to promote bone repair, but the implanted cells have a small chance of surviving because they are not prepared for a lack of oxygen and nutrients at the fracture site.

Breakthrough in generating embryonic cells that are critical for human health
Neural crest cells arise early in the development of vertebrates, migrate extensively through the embryo, and differentiate to give rise to a wide array of diverse derivatives.
More Homeostasis Current Events and Homeostasis News Articles

Allostasis, Homeostasis, and the Costs of Physiological Adaptation

Allostasis, Homeostasis, and the Costs of Physiological Adaptation
by Jay Schulkin (Editor)


In contrast to homeostasis, allostasis refers to the relatively new idea of "viability through change." This book addresses basic physiological regulatory systems, and examines bodily regulation under duress. It integrates the basic concepts of physiological homeostasis with disorders such as depression, stress, anxiety and addiction. It will interest graduate students, medical students, and researchers in physiology, epidemiology, endocrinology, neuroendocrinology, neuroscience, and psychology.

Homeostasis Lost (Volume 1)

Homeostasis Lost (Volume 1)
by Kyan Yauchler (Author)


Morning breaks with eerie silence in the rural Midwest. Jake, Maggie, and Don each wake one late spring morning to find that nothing works—phones, cars, clocks. Everything involving electricity is dead. As the reality of what has happened comes to light, they begin to leave their homes, some in search of answers, others in desperate need of help. People around them are dying, planes are crashing, riots are forming, and no one can do anything about it. The three eventually cross paths and head into an uncertain future together in hopes of again finding balance—homeostasis—in this new world without power. That is, if they can survive.

Homeostasis: The Journey of a Manic-Depressive

Homeostasis: The Journey of a Manic-Depressive
by Donald Rodriguez (Author), Penelope Rodriguez (Contributor)


Donald Rodriguez takes readers on a roller-coaster ride as he shares what it means to live with Bipolar 1 Disorder. When manic episodes began to creep into his life, he put his family through hell and risked his own life in the process. Meanwhile, he loaded up on the toughest classes he could take as a premed student at Boston University, joined a fraternity, played for the club hockey team, and took on more than he could handle. His family physician prescribed him Adderall to focus and Trazodone to sleep. Rodriguez also started taking Prozac because his doctor thought he had situational depression because his grandma had died, his longtime girlfriend had dumped him, and his college coursework was stressing him out. Injuries had also forced him to stop playing hockey. In short order, he...

OCR A-Level Year 2 Biology A Workbook: Communication, Homeostasis and Energy (Topic 8); Genetics, Evolution and Ecosystems

OCR A-Level Year 2 Biology A Workbook: Communication, Homeostasis and Energy (Topic 8); Genetics, Evolution and Ecosystems
by Jenny Wakefield-Warren (Author)


Our Student Workbooks build students understanding, developing the confidence and exam skills they need, whilst providing ready-prepared lesson solutions. * Supplements key resources such as textbooks to adapt easily to existing schemes of work * Offers time-saving and economical lesson solutions for both specialist and non-specialist teachers * Provides flexible resource material to reinforce and apply topic understanding throughout the course, as classwork or extension tasks, or with revision * Creates opportunities for self-directed learning and assessment with answers to tasks and activities supplied online * Prepares students to meet the demands of the specification by practising exam technique and developing their literacy skills

A Question of Balance: Homeostasis and metabolism: an upregulatory and downregulatory model

A Question of Balance: Homeostasis and metabolism: an upregulatory and downregulatory model


Why do a small number of people appear to be physiologically overly sensitive or reactive to the modern world? Current medical models can offer no satisfactory mechanism for hypersensitivity and other “medically unexplained syndromes” as they are sometimes termed.
Driven by personal experience the author seeks to find some form of scientific explanation for the development of hypersensitivity to chemicals, foods and man-made electromagnetic radiation. Investigation over a range of scientific research suggests the possibility of such a model.
This short book examines a variety of topics that are involved in the development of this model:
–homeostasis and allostasis
–receptor dysregulation
–dopamine, addiction and similarities with a modern diet of highly...

Yoga & Meditation: A Holistic Approach to Perfect Homeostasis

Yoga & Meditation: A Holistic Approach to Perfect Homeostasis
by Yogini Shubh Veer (Author)


Learn how to relax your body and mind and give yourself a great refreshing lift with Yoga and Meditation Author Dr Yogini Shubh Veer has been teaching yoga and meditation for over 4 decades and in Yoga & Meditation she shares her rich experience to help you restore your physical and mental balance.You'll learn the basics of life: Breathing, pranayama and prana, diet, ethics, relaxation, concentration and will discover how each one has an impact on your daily life. In clear simple language, the intricacies of yoga and meditation are explained. 108 yoga postures with some 400 step-by-step illustrations and instructions are included - including the complete 'Surya Namaskar', Salutation to the sun, 24 postures in one. Lessons on relaxation will help to ease any tension and depression and...

Permanent Weight Loss: How to Utilize Homeostasis and Lose Weight for Good: Lose Weight Permanently

Permanent Weight Loss: How to Utilize Homeostasis and Lose Weight for Good: Lose Weight Permanently


Permanent Weight Loss: How to Utilize Homeostasis and Lose Weight for Good

This book is a guide that will show you how to use your own body and its mechanisms to permanently lose weight.
 
I will explain to you why overweight people stay overweight and tell you how to snap out of this cycle.
You'll also find out about homeostasis, one of the most important yet frequently forgotten pieces to the weight loss puzzle.
WHO IS THIS BOOK FOR?
This book is for people who is stuck in the lose/gain weight cycleThis book is for someone who would like to lose weight and keep it offThis book is for people who want to understand the mechanism behind weight gain loss and gain and can use this knowledge to gain advantage and succeed at their weight loss goals.
Autumn Nation (Homeostasis Lost) (Volume 2)

Autumn Nation (Homeostasis Lost) (Volume 2)
by Kyan Yauchler (Author)


The harrowing journey continues for Jake, Maggie, and Don in the sequel to Homeostasis Lost. The new family has found a home, but a new threat is upon them and one that cannot be ignored. The invasion has begun. As they continue to survive in a world without power, people around them are growing hungry and aggressive, and foreign troops are getting closer. The season of warmth and certainty is waning, and a cold and deadly winter is on its way. They have become part of an Autumn Nation—one that hopes to someday again see spring.

Biology: Homeostasis of Body Temperature and Water Levels

Biology: Homeostasis of Body Temperature and Water Levels


Homeostasis is one of the most important principles of biology. Animals need to maintain a relatively stable internal state in order to function effectively. Enzymes need to be kept at close to their optimum temperature and cells require the right amount of water.
This book focuses on the homeostatic control of both body temperature through the co-ordinating action of the hypothalamus; and of water levels with emphasis on the function of the kidney.
Some of the facts about the homeostatic control of water levels are really astonishing. For example, about three hundred litres of blood pass through the kidneys every day, creating about two hundred litres of filtrate - most of which the kidney reabsorbs into the blood, resulting in about three quarters of a litre of urine being...

Homeostasis

Homeostasis
by Felipe Monsalve (Author)




© 2017 BrightSurf.com