La surproduction de la cycline D1 et son inhibition.

6 juin 2013

Richard Finn, MD, Division of Hematology/Oncology at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, describes the potential impact of the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib (PD-0332991) in the treatment of patients with ER-positive metastatic breast cancer.

(Il y a une vidéo ou le médecin décrit les bienfait du médicament)

Finn believes palbociclib holds the potential to be a game changer in the treatment of patients with ER-positive breast cancer. If approved, this agent would be the first indication for a CDK inhibitor. Additionally, he believes, if the magnitude of benefit observed in the phase II trial holds true in the phase III, treatment with this agent will likely become the new standard of care.

Finn croit que le palbociclib est un médicament qui peut changer bien des choses dans les traitements des patientes avec le cancer du ER positif . S'il est approuvé, cet agent sera le premier comme inhibiteur de CDK. De plus, il croit que si les résultats observés dans la phase II se maintiennent dans la phase III, le traitment avec cet agenr sera le nouveau standard.

The traditional treatment approach in breast cancer involves the sequencing of several active agents across multiple lines of therapy. However, the biggest advantage is generally derived from the agents administered in the first-line. Given the significant improvement in progression-free survival of 18.6 months in the phase II trial comparing palbociclib plus letrozole to letrozole alone it is hard not to view this agent as a potential new standard of care, Finn states.

L'approche traditionnelle dans le traitement du cancer du implique une suite de plusieurs agents à travers plusieurs lignes de thérapie. toutefois le plus gros avantage est généralement dû aux agents de première ligne. Étant donné l'amélioration significative de 18.6 mois de survie sans la maladie dans la phase II qui comparait le palbociclib + letrozole au letrozole seul c'est difficile de ne pas voir cet agent comme le nouveua standard.

Importantly, Finn believes, treatment with palbociclib is well tolerated. This represents a huge advantage by improving efficacy without increasing toxicity and opens the door to a variety of further possibilities. The ultimate goal of research, Finn states, is to move this agent into the treatment of patients with early-stage breast cancer. - See more at: http://www.onclive.com/onclive-tv/dr-finn-on-the-future-of-palbociclib-in-breast-cancer#sthash.IMH8pLoe.dpuf

Finn croit que le traitement avec le palbociclib est bien toléré. Cela représent eun énorme avantage pour améliorer l'efficacité sans augmenter la toxicité et ouvre la porte à beaucoup de possibilité futurs. Le but lutime est de donner cet agent à des patientes avec des stages précoces du cancer du

(Oct. 16, 2012) — In what they say is a promising and highly selective treatment strategy, scientists at Dana-Farber Cancer Institute have safely shut down breast cancer and a form of leukemia in mice by targeting abnormal proteins to which the cancers are "addicted," according to a new study.

D'après ce que disent les scientifiques du Centre Dana Faber au sujet d'un traitement hautement sélectif, ils ont, de façon sécuritaire arrêter un cancer du et une forme de leucémie chez des souris en ciblant des protéines anormales desquelles le cancer est dépendant.

Even though the investigators genetically silenced the proteins or blocked them with a drug in normal as well as cancerous tissues, the animals remained healthy, they report in the Oct. 16 issue of the journal Cancer Cell. Peter Sicinski, MD, PhD, of Dana-Farber is the paper's senior author.

Même si les chercheurs rendent silencieuses les protéines ou les bloquent avec un médicament dans les tissus cancéreux aussi bien que normaux, les animaux restent en santé.

The experiments targeted two related proteins, cyclin D1 and cyclin D3, that control cells' growth cycle. Many types of cancer have abnormal amounts of the proteins, spurring the cells to grow too rapidly and form tumors. The new results shown that the cancers' addiction to these proteins is an Achilles' heel that can be safely targeted with an inhibitor drug that halts cancer growth or causes cancer cells to die.

Les expériences concernent deux protéines, la cyclin D1 et la cyclin D3, qui contrôlent le cycle de la croissance cellulaire. Plusieurs types de cancers ont trop de ces protéines. ça poussent les cellules à croitre trop rapidement et à former des tumeurs. Les nouveaux résultats ont mnontré que la dépendance des cancers à ces protéines est le talon d'Achille qui peut être ciblé de façon sécuritaire avec un inhibiteur qui arrête la croissance ou fait que les cellules meurent.

Based on the results, the Dana-Farber scientists are planning a clinical trial, using an experimental cyclin-inhibiting drug called PD0332991 that has already been tested in a form of lymphoma.

Basé sur ces résultats, les scientifiques planifient un essai clinique (sur des humains) qui utilisera un médicament expérimental qui inhibe les cyclines appel PD0332991 qui est déjà testé pour une forme de lymphome.

"It was impressive to find that you could target a single cyclin protein and completely clear the leukemia and the mouse remained healthy," said Yoon Jong Choi, PhD, the study's lead author. "We're excited because we think this approach is very promising" as a potential treatment for some cancer types, she added.

"Ça a été impressionnant de découvrir que cibler une simple protéine cycline peut éliminer complètement la leucémie et garder la souris en santé. Nous sommes excités parce que nous pensons que cette approche est très prometteuse comme traitement pour le cancer."

Some of the experimental mice had been engineered to develop a type of breast cancer driven by the ErbB2 oncogene. Others were modified to develop a type of T-cell acute lymphoblastic leukemia (T-ALL) that is driven by an abnormal pathway known as Notch1. In one experiment, human T-ALL cells were infused into mice that then developed the disease.

Quelques unes des souris expérimentales ont été faites pour développer un type de cancer du sein mené par l'oncogène Erb2. D'autres ont été modifié pour développer une leucémie lymphoblastique aigue qui est menée par une gène nommé Notch1. Dans une expérience le cancer a été infusé dans les souris.

Blocking cyclin D1 in the mice drove the breast cancer cells into a kind of permanent retirement called senescence, an irreversible halt to their growth cycle. Inhibiting cyclin D3 in the T-ALL leukemia mice caused the cancer cells to self-destruct -- a programmed death process called apoptosis.

Bloquer la cycline D1 dans les souris avec le cancer du sein conduit les cellules à se retirer dans la senescence (état réversible mais qui arrête la croissance ) Inhiber les cycline D3 causes les cellules de la leucémie T-ALL
fait que les cellules de ce cancer se détruisent elles-mêmes (apoptose).

In addition to these tests with mouse cancers, the scientists found that the cyclin-D-inhibiting drug had similar effects on human blood cancer cells in the laboratory.

En plus, de ces tests avec les souris cancéreuses. les scientifiques ont découvert que l'inhibition de la cycline D a des effets similaires sur les cellules de sang humain en laboratoire.

Cyclin proteins act as "checkpoint" guards to control cell's cycle of rest, growth and division. The D-cyclins determine when a cell begins making DNA in preparation for dividing to form new cells. In many types of cancer, an excess of cyclins allows cells to grow too fast and form tumors. Abnormal cyclins D1, D2 and D3 are found in breast, lung, endometrial, pancreatic, and testicular cancers and in multiple myeloma and other blood cancers.
etc.

In a key report in Nature in 2001, Sicinski showed that mice engineered to lack cyclin D1 were resistant to developing breast cancer. It wasn't known for many years, however, whether knocking out cyclin D1 could halt an established cancer, or if breast cancer needed the protein long-term.

Also unknown was whether normal cells could get along without cyclin D1: If not, treating cancer by targeting the protein might be too dangerous.

To test these questions, Choi and her Dana-Farber colleagues developed a strain of mice with cyclin D proteins that could be inactivated at any time by treating the mice with the drug tamoxifen.

"By generating these 'conditional' knockout mice, we could address these questions for the first time," said Choi. The effect was global, affecting all the body cells, not just those that were cancerous. When the cyclin D proteins were turned off using this technique, the addicted cancer cells shut down while normal cells were unaffected.

The authors say the results show that blocking cyclin D "represents a highly selective anticancer strategy that specifically targets cancer cells without significantly affecting normal tissues."

Other authors of the report include Xiaoyu Li, MD, PhD, a co-first author, and Harald von Boehmer, MD, PhD, of Dana-Farber, and Andrew L. Kung, MD, PhD, formerly at Dana-Farber and now at Columbia University.

(Nov. 15, 2008) — Breast cancer stem cells are known to be involved in therapy resistance and the recurrence of cancerous tumors. A new study appearing in Clinical and Translational Science shows the mechanisms governing stem cell expansion in breast cancer (called Notch activity), and finds that therapy targeting a protein called cyclin D1 may block the expansion of cancerous stem cells.

Les cellules souches du cancer du sont connues pour être impliquées dans la résistance à la thérapie et dans la récurence des tumeurs cancéreuses. Une nouvelle étude montre les mécanismes qui gouvernent l'expantion des cellules souches dans le cancer du sein (appelé activité de Notch) et démontre qu'une thérapie ciblant la protéine cyclin d1 peut bloquer l'expansion des cellules cancéreuses.



The study, conducted by Dr. Richard Pestell and colleagues at Thomas Jefferson University, was the first to show that cyclin d1 is required for breast cancer growth in mice. As cyclin d1 is known to be over-expressed in human breast cancer, the findings may explain how cyclin d1 contributes to breast tumor growth, and provide the rationale for targeted therapies at cancerous stem cells in humans.

L'étude était la première a démontré que la protéine cyclin d1 était requise pour la croissance du cancer du sein chez les souris. Comme la cyclin d1 est connue pour être sur-exprimée chez les humains ayant le cancer du sein, la découverte pourrait expliquer comment la cyclin d1 contribue à la croissance du cancer du sein et fournir la raison de cibler avec des thérapies les cellules souches cancéreuses chez l'humain.

"Breast and other cancers are maintained through a population of cancer stem cells. By specifically targeting cancer stem cells we hope to reduce recurrence and improve therapy responses," says Pestell.

"Le cancer du sein et d'autres cancers se perpétuent à travers une population de cellules souches cancéreuses aussi en ciblant ces cellules nous espérons réduire les récurences et améliorer les réponses à la thérapie."

Cancer arises as a result of the accumulation of multiple genetic lesions that ultimately result in unregulated cell cycle, and Notch activity is a key determinant of the cellular development and differentiation related to this process. As Notch signaling is activated in human breast cancer, (and a negative regulator of Notch signaling reduces the disease), the molecular mechanisms regulating Notch activity are of fundamental importance for future therapy.

Les mécanismes qui régulent le gène Notch sont d'une importance fondamentale pour les futures thérapies.

(Jan. 16, 2008) — Researchers at Lombardi Comprehensive Cancer Center at Georgetown University Medical Center have shown why a protein known as cyclin D1 may be the Achilles heel for breast tumors that are estrogen receptor positive (ER+) − which is the most common type of breast cancer.

Les chercheurs ont démontré pourquoi une protéine connue sous le nom de cycline D1 peut être le talon d'Achille du cancer du qui sont ER+ positif, ce qui est le plus commun des cancers du sein.

In the December 10th online edition of the journal Oncogene, investigators say the findings support testing an experimental class of drugs that aim to inhibit the cyclin D1 protein in women with ER+ breast cancers. These agents are currently being tested in this disease as well as in many other types of cancer, the researchers say, and the study provides additional molecular support for their use in breast cancer.

Dans l'édition du 10 décembre du Journal Oncogene, les chercheurs disent que leurs découvertes supportent le besoin de la mise au point d'un médicament pour cibler la cycline D1 ches les femmes avec le cancer du sein ER+. Ces agents sont couramment testés pour cette maladie aussi bien que pour d'autres types de cancers mais leurs recherches fournissent des molécules additionnelles pour être utiliser contre le cancer du

“Everyone knows that cyclin D1 is a huge player in breast cancer, but no one has shown what happens when cyclin D1 is absent at the same time that the estrogen receptor is being over-expressed on tumors. Now we know the answers, and we hope these insights help further our understanding and treatment of breast cancer,” said the study’s lead author, Maria Silvina Frech, Ph.D., who is currently a postdoctoral researcher at the National Cancer Institute but who worked on the study at Georgetown.

"Tout le monde sait que la cycline D est un joueur important dans le cancer du sein mais personne n'a démontré ce qui arrive lorsque la cycline D1 est absente en même temps que le récepteur d'oestrogène est surexprimé sur la tumeur. Maintenant nous savons la réponse et nous espérons que ces nouvelles données aidera notre future compréhension du cancer du sein et son traitement." a dit MAria Silvina Frech.

“These findings give insight into how drugs that indirectly inhibit cyclin D1 function, either those in testing or ones to be developed, might help a significant number of women with breast cancer,” said Priscilla Furth, M.D., a professor at the Lombardi Comprehensive Cancer Center who is the study’s senior investigator.

Cyclin D1 belongs to a family of cyclin genes whose proteins regulate cyclin-dependent kinases (CDKs), which in turn control cell division. CDKs are the main facilitators of cell proliferation cycle. Over-production of the Cyclin D1 protein or amplification (extra copies) of the gene have been observed in a number of cancers, and this study continued a body of research in Furth’s lab that has examined the relationship between ER+ breast cancer and cyclin D1.

La surproduction de cycline D a été observé dans beaucoup de cancers.

In 2005 Furth and Frech published a study that demonstrated that over expression of ERα (the main estrogen receptor subtype that mediates cell growth and is the major player in ER+ breast cancer) in mice resulted in the development of the earliest form of breast cancer, ductal carcinoma in situ (DCIS). They then found that cyclin D1 was over expressed in these lesions but not in the surrounding normal tissue. “Once the cancer process begins, cyclin D1 starts being over-expressed,” Frech said. “This was an exciting finding, but it was not clear what the precise role cyclin D1 plays in ER+ cancer.”

To find out what the protein was doing in these breast tumors, Frech, Furth, Kathleen Torre, B.S., from Georgetown and Gertraud W Robinson, Ph.D. from NIDDK, NIH, decided to take a genetics approach to the problem. They created an animal model that both over-expressed ERα and lacked cyclin D1.

They thought they would see a decreased incidence in DCIS in the animals, but what they actually found was that they completely lacked the mammary gland tissue that normally encases breast milk ducts. “This was very surprising. Most of the cells that usually make up the gland were absent, replaced by other structural tissue that shouldn’t be there,” she said.

t was also puzzling, Frech said, because puberty-induced mammary gland development in female mice that simply lack cyclin D1 is essentially normal. It made no sense to researchers that coupling over expression of ERα with the absence of cyclin D1 would have a complete lack of mammary glands. “This was striking, very unusual,” she said.

The solution was also very challenging, said Frech, whose three years of work on the project earned her a Ph.D. They eventually found that when cyclin D1 is deleted, levels of another major cyclin family member − cyclin E − are increased. And over-production of cyclin E, in the developing gland of these ERα over expressing mice led to DNA damage and cell death. The question that remains unanswered is whether this situation would hold true in advanced cancers treated with agents that inhibit cyclin D1 function, she said.

They also discovered that while cyclin D1 was not necessary for maintenance of normal breast cells, it was essential for the proliferation of abnormal mammary gland cells − and this differential use of cyclin D1 seems to be unique to early breast cancer. “That supports the idea that reducing cyclin D1 in breast cancer cells would not harm normal cells,” she said. There are experimental agents now being tested in clinical trials that shut down cyclin D1 function by targeting CDKs, Frech said. For example, flavopiridol is a potent CDK inhibitor currently undergoing clinical trials for a variety of tumors including breast cancer. Clinical activity is encouraging when used in combination with other molecular targeted agents, she said.

The study was supported by grants from the Department of Defense and the National Institutes of Health.