Cancer Moonshot - inmunoterapia

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Sab, 13 Ene 2018, 03:56

Las variantes genéticas determinan el microambiente y la inmunidad de un tumor
engineered mice models to represent four distinct known genetic variations of human prostate cancer. The models lacked either Pten alone or in combination with other genetic alterations known to drive the disease.

profound differences in the types and relative numbers of the immune cells that had accumulated in and around the tumor

genetic model lacking both Pten and the tumor suppressor gene called Trp53 demonstrated an increased accumulation of myeloid cells, the immune cells that mediate immunosuppression.

In stark contrast, tumors from the genetic model lacking Pten and a different tumor suppressor gene called PML lacked intratumoral immune infiltration

Different tumors secreted distinct chemical attractants, which in turn recruited - or didn't recruit, in the case of the immune-desert tumors - different immune cell types into the tumor. Critically, the immune cells recruited to the tumors were found to be essential in supporting the growth and progression of these tumors.
https://www.nature.com/articles/nm.4463
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Vie, 19 Ene 2018, 16:09

Impresionante lectura. ¿Que dirige la metástasis?
When he injected chromosomally unstable tumor cells into mice, he indeed found that they were many times more likely to spread and form new tumors than tumor cells in which chromosomal instability was suppressed. That was true even though both sets of tumor cells started out genetically identical, with the same abnormal numbers of chromosomes, suggesting that chromosomal instability itself was a driver of metastasis.

The researchers examined gene activity in these two sets of tumor cells. They found that those with high chromosomal instability had abnormally elevated activity stemming from more than 1,500 genes—particularly in ones involved in inflammation and the response of the immune system to viral infections. "These were cancer cells cultured in a dish, not in the presence of any immune cells," Dr. Bakhoum said. "We were very surprised by that and wondered what could be driving this inflammatory reaction."

Recent studies by other laboratories offered some clues: Chromosomes in unstable tumor cells can sometimes leak out of the cell nucleus where they normally reside. These mis-located chromosomes encapsulate themselves to form "micronuclei" in the fluid, or cytosol, in the main part of the cell outside of the main nucleus. However, micronuclei tend to rupture eventually, releasing naked DNA into the cytosol.

Cells interpret DNA in the cytosol as a sign of an infecting virus, which typically releases its DNA in the cytoplasm when it first attacks a cell. Human cells have evolved to fight this type of viral infection by sensing naked cytosolic DNA using a molecular machine called the cGAS-STING pathway. Once activated, this pathway triggers an inflammatory antiviral program.

Dr. Bakhoum and colleagues examined their chromosomally unstable tumor cells, and found that they did indeed have plenty of cytosolic DNA—and showed evidence of chronic activation of the anti-viral cGAS-STING proteins. Lowering cGAS-STING levels reduced inflammation and prevented the ability of otherwise aggressive tumor cells to metastasize when injected into mice.
https://medicalxpress.com/news/2018-01- ... anism.html
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Vie, 19 Ene 2018, 17:33

BRAF y MEK como neoadyuvante, buenos resultados en melanoma fase 3.
interim data analysis occurred after 21 patients were treated.

At a median follow-up time of 18.6 months:

All seven treated with standard of care surgery had their disease progress, with median time to progression at 2.9 months.
Of 14 randomized to the neoadjuvant combination, four progressed, with median time to progression of 19.7 months.
Of the seven patients who achieved a pathological complete response after presurgical therapy, none experienced distant disease relapse.
Median overall survival had not been reached in either arm.

Most melanoma is detected at early stages and treated successfully with surgery, but about 15 percent of patients progress to stage 3, when the disease has spread to lymph nodes.
https://www.newswise.com/articles/presu ... 3-melanoma


Parece que el cancer de piel es uno de los grandes beneficiados en estos años
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Mié, 24 Ene 2018, 14:40

Mantener las metástasis en estado latente via MSK1
MSK1 as a key regulator of dormant or latent metastases. Using clinical samples from patients, the scientists confirmed that ER + breast cancer tumours that do not express MSK1 are associated with a risk of earlier relapse, while those that express it will form metastases later
https://www.nature.com/articles/s41556-017-0021-z
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Jue, 01 Feb 2018, 05:52

Combinación de inmunoterapia a baja dosis a nivel local cura distintos tipos de cáncer en ratones.
Using this assay, the combination of unmethylated CG–enriched oligodeoxynucleotide (CpG)—a Toll-like receptor 9 (TLR9) ligand—and anti-OX40 antibody provided the most impressive results. TLRs are components of the innate immune system that recognize molecular patterns on pathogens. Low doses of CpG injected into a tumor induce the expression of OX40 on CD4+ T cells in the microenvironment in mouse or human tumors. An agonistic anti-OX40 antibody can then trigger a T cell immune response, which is specific to the antigens of the injected tumor. Remarkably, this combination of a TLR ligand and an anti-OX40 antibody can cure multiple types of cancer and prevent spontaneous genetically driven cancers
http://stm.sciencemag.org/content/10/426/eaan4488



La de veces que hemos curado el cáncer en ratones. Alguna tendrá que ser buena.
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Fisio
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Jue, 01 Feb 2018, 16:25

Neoadyuvante en melanoma avanzado con mutación BRAF (60%)
surgically removable stage III or stage IV melanoma with a mutation of the BRAF gene

Currently less than 50 percent of individuals in this high-risk category are alive, five years after diagnosis.
patients receiving the neoadjuvant therapy were doing much better, but 58% of them had a complete pathologic response. That means that when their tumor was removed it had no viable cancer cells in it,
https://medicalxpress.com/news/2018-02- ... tment.html
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Mié, 07 Feb 2018, 01:43

Evasión de células tumorales sin mutaciones: cambios estructurales en proteinas
changes in a cancer cell's cytoskeleton and shape often enhance its ability to invade surrounding tissues and can lead to metastasis throughout the body.

"People have long associated changes in the extracellular matrix with tumor progression or resistance to drugs," Whitson said. "But this is the first time anyone has identified the molecular causes behind this link. Now we know that we can use the presence of nuclear MKL1 as a biomarker to identify patients who might benefit more from MKL1 or GLI1 inhibitors than from vismodegib
https://www.nature.com/articles/nm.4476
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Vie, 09 Feb 2018, 02:21

El retorno de la angiogénesis (LTBP3)
Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are important for the secretion, activation, and function of mature TGFβ, especially so in cancer cell physiology. However, specific roles of the LTBPs remain understudied in the context of the primary tumor microenvironment. Herein, we investigated the role of LTBP3 in the distinct processes involved in cancer metastasis
https://www.nature.com/articles/s41388-017-0075-1


Muchos investigadores notables pensaron que los antineoangiogénicos acabarían con el cancer.
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Vie, 09 Feb 2018, 03:22

Resistencia al tumor: cuando el cancer aprende a escupir las drogas (bombas transmembrana). Nanopartículas para bloquear las mitocondrias y la producción de ATP que necesitan estas bombas
nanoparticle that targets mitochondria through pyruvate, to specifically produce reactive oxygen species (ROS) in mitochondria under near-infrared (NIR) laser irradiation. The ROS can oxidize the NADH into NAD+ to reduce the amount of ATP available for the efflux pumps. The treatment with LSC nanoparticles and NIR laser irradiation also reduces the expression and increases the intracellular distribution of the efflux pumps. Consequently, multidrug-resistant cancer cells lose their multidrug resistance capability for at least 5 days, creating a therapeutic window for chemotherapy
https://www.nature.com/articles/s41467-018-02915-8
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Jue, 15 Feb 2018, 22:05

Cancer de colon sin buena respuesta a inmunoterapias. Mecanismo de evasión:
Increased TGFβ in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion
https://www.nature.com/articles/nature25492
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