FDA grants RET inhibitor breakthrough therapy designation for lung, thyroid cancers


The FDA granted breakthrough therapy designation to LOXO-292, a selective RET inhibitor, for the treatment certain patients with RET-altered non-small cell lung cancer or medullary thyroid cancer, according to the agent’s manufacturer.

The designation includes patients with RET-fusion positive NSCLC who have progressed on platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor, and patients with RET-mutant thyroid cancer who have progressed following prior treatment and have no alternative treatment options.

The FDA based the breakthrough designation of LOXO-292 (Loxo Oncology) on the ongoing phase 1/phase 2 LIBRETTO-001 clinical trial of patients with RET-altered advanced solid tumors.

“We look forward to working with FDA to streamline the development of LOXO-292 in the two patient populations that have comprised the bulk of our initial clinical trial enrollment,” Josh Bilenker, MD, CEO of Loxo Oncology, said in a company-issued press release. “Given the many available therapies for non-small cell lung cancer and medullary thyroid cancer, we are pleased that LOXO-292 has shown encouraging data in refractory patients and hope to demonstrate the full potential of this treatment in additional populations over time.”

Nerve cells actively repress alternative cell fates, researchers find


A neural cell maintains its identity by actively suppressing the expression of genes associated with non-neuronal cell types, including skin, heart, lung, cartilage and liver, according to a study by researchers at the Stanford University School of Medicine.

 It does so with a powerful . “When this protein is missing, neural cells get a little confused,” said Marius Wernig, MD, associate professor of pathology. “They become less efficient at transmitting nerve signals and begin to express genes associated with other cell fates.”

The study marks the first identification of a near-global repressor that works to block many cell fates but one. It also suggests the possibility of a network of as-yet-unidentified master regulators specific to each cell type in the body.

“The concept of an inverse master regulator, one that represses many different developmental programs rather than activating a single program, is a unique way to control neuronal cell identity, and a completely new paradigm as to how cells maintain their throughout an organism’s lifetime,” Wernig said.

Because the protein, Myt1l, has been found to be mutated in people with autism, schizophrenia and major depression, the discovered mode of action may provide new opportunities for therapeutic intervention for these conditions, the researchers said.

Wernig is the senior author of the study, which will be published online April 5 in Nature. Postdoctoral scholars Moritz Mall, PhD, and Michael Kareta, PhD, are the lead authors.

Repressors

Myt1l is not the only protein known to repress certain cell fates. But most other known repressors specifically block only one type of developmental program, rather than many. For example, a well-known repressor called REST is known to block the neuronal pathway, but no others.

“Until now, researchers have focused only on identifying these types of single-lineage repressors,” said Wernig. “The concept of an ‘everything but’ repressor is entirely new.”

In 2010, Wernig showed that it is possible to convert skin into functional neurons over the course of three weeks by exposing them to a combination of just three proteins that are typically expressed in neurons. This “direct reprogramming” bypassed a step called induced pluripotency that many scientists had thought was necessary to transform one cell type into another.

 One of the proteins necessary to accomplish the transformation of skin to neurons was Myt1l. But until this study the researchers were unaware precisely how it functioned.

“Usually we think in terms about what regulatory programs need to be activated to direct a cell to a specific developmental state,” said Wernig. “So we were surprised when we took a closer look and saw that Myt1l was actually suppressing the expression of many genes.”

These genes, the researchers found, encoded proteins important for the development of lung, heart, liver, cartilage and other types of non-neuronal tissue. Furthermore, two of the proteins, Notch and Wnt, are known to actively block neurogenesis in the developing brain.

Blocking Myt1l expression in the brains of embryonic mice reduced the number of mature neurons that developed in the animals. Furthermore, knocking down Myt1l expression in mature neurons caused them to express lower-than-normal levels of neural-specific genes and to fire less readily in response to an electrical pulse.

‘A perfect team’

Wernig and his colleagues contrasted the effect of Myt1l with that of another protein called Ascl1, which is required to directly reprogram skin fibroblasts into neurons. Ascl1 is known to specifically induce the expression of neuronal genes in the fibroblasts.

“Together, these proteins work as a perfect team to funnel a developing cell, or a cell that is being reprogrammed, into the desired cell fate,” said Wernig. “It’s a beautiful scenario that both blocks the fibroblast program and promotes the neuronal program. My gut feeling would be that there are many more master repressors like Myt1l to be found for specific cell types, each of which would block all but one cell fate.”

Source:medicalxpress.com

Stem Cells Converted Into Lung Tissue.


Lung transplant recipients have a relatively low 10 year survival rate of about 28%. Cellular rejection of the donor organ occurs about 90% of the time, which brings additional obstacles for the patient and doctors. This might be about to change, as functional lung tissue has been created from human stem cells. The research comes from Hans-Willem Snoeck from the Columbia Center for Translational Immunology and was published in the current edition of Nature Biotechnology.

A couple of years ago, Dr. Snoeck was able to convert stem cells into the precursor endoderm cells that can eventually differentiate into lung cells. This was done with human embryonic stem cells as well as human induced pluripotent stem cells, which involve a bit more work but are easier to come by. Those precursor cells were shown to actually differentiate into six different respiratory tissues, including the coveted type II alveolar cells. which facilitate gas exchange and produce surfactant.

Type 2 alveolar cells, also called pneumocytes, are responsible for producing surfactant, the compound that allows the lungs to remain inflated with air. These type II cells also aid in gas exchange and lung repair.

The lung tissue produced by stem cells could give researchers a unique perspective to study the tissue and learn more about how lung diseases originate. This could lead to better treatment options for lung diseases.

If treatments do not work and transplant becomes inevitable, physicians can use the patient’s own cells to provide a new disease-free organ. This eliminates both the potential for cellular rejection as well as the stress of waiting on the transplant list. To make a replacement lung, researchers would first remove the patient’s lung and decellularize it, leaving only a cartilaginous scaffold. The stem cells would then be used to coat the scaffold and regrow functional tissue to be put back into the patient.

Though it is a long way from getting implanted into a human body, these results are exciting. A patent has been filed by Columbia University for their technique of converting induced pluripotent stem cells into the functional tissue.

Stop smoking, stay good-looking.


If bad lungs don't scare you then this should. Screenshot: tobaccobody.fi
If bad lungs don’t scare you then this should.
A public health agency in Finland is using an interesting approach to shock teens into not smoking

The Tobacco Body website features an interactive image of a man and a woman. Users zoom in and out of their body parts to observe the effects smoking has on a male and female body.

This is a new campaign by the Cancer Society of Finland, whose objective, according to the website of their ad agency, is to use this as a tool to show teenagers “to think critically about smoking.” The idea is to move beyond the black lungs, gooey tar and damaged livers, and use technology to “make the shock effect more shocking.”

And pretty shocking it is. Before-lady and Before-man are indeed much better-looking than After-lady and the After-man.

The strategy employed is clear: teens today don’t care about lungs, livers and cancer, or if they do, the constant exposure to such warnings has rendered them ineffective. What they do care about is appearances. So let’s show them how ugly smoking makes them.

On one hand you can’t argue with facts: smoking does give you spots, increase your testosterone levels, give you bad breath and unhealthy hair, yellow your teeth and nails, etc. Fact-wise there’s not much to dispute in the Tobacco Body website. But how advisable is it to resort to telling teenagers what is beautiful/popular/acceptable and what is not, even if it is towards the noble cause of telling them to not smoke?

Sample these snippets taken from the website:

[Man & Woman] “Dear Smoker, we’re sorry to inform you that according to nail fashion experts, nicotine yellow is not this season’s colour.”

[Woman] “Hey non-smoking girl, you are on a wonder-diet and you don’t even know it! Your body shape is closer to the average, whereas research shows that smokers weigh more and are rounder around the abdominal area.”

[Woman] “The non-smoking woman is less-likely to have as much hair growing on her arms as a smoker.”

[Woman] “The non-smoking woman usually has no additional hairs growing under her nose… No need for a five-bladed special razor.”

[Man & Woman] “Smokers have bad breath. As many as 20 per cent of people have ended relationships because of smoking. In Burn Magazine’s interviews several celebrities reveal they prefer kissing non-smokers.”

[Man & Woman] “A weary face is not a popular one: out of the 100 most popular profile pictures in a dating service only 2 were pictures of smokers.”

Basically, the Cancer Society of Finland is telling youngsters that smoking makes you hairy, fat, yellow-toothed and gives you bad breath. I found it slightly bothersome how features that are quite normal in several healthy teenagers, like rounded abdomens and hair on arms (for women), was being grouped with those which are blatantly undesirable and unhealthy, like yellowing teeth, bad breath and damaged lungs.

I wondered if this ad could be sending negative body image messages to kids who are naturally fat or hairy – are they implying that these kids are not as desirable?

But the more I thought about it the harder I realised it was to completely buy into that line of reasoning. Because, as a friend pointed out, this may be a case where the end could perhaps justify the means.

It was different in the case of the Dove ‘You’re more beautiful than you think you are’ campaign which also used a similar strategy to sell their product. They too inadvertently (?) went about setting definitions for beauty. The glaring difference of course was that Dove, at the end of the day, was trying to sell us soap under the guise of the noble motive of wanting women to feel good about themselves.

In the case of Tobacco Body, there’s no such deception. As questionable as their strategy might be, we can probably be sure that all this campaign wants is for teenagers to say no to smoking. They are, after all, the Cancer Society of Finland.

A Small RNA That Promotes Lung Cancer.


Gene expression in both healthy and cancerous tissues is controlled by a wide array of regulatory molecules including a group of small RNA molecules known as microRNAs. New research, performed by Ethan Dmitrovsky and colleagues, at Dartmouth Medical School, Hanover, now provides evidence that the microRNA miR-31 promotes lung cancer by repressing the expression of a number of tumor suppressor genes (i.e., genes that generate proteins that suppress the development of cancer).

The initial series of experiments conducted in the study indicated that miR-136, miR-376a, and miR-31 were all overexpressed in mouse and human malignant lung tissue compared with paired normal tissue. Importantly, knockdown of miR-31 expression repressed the in vitro growth of mouse and human lung cancer cell lines and reduced the in vivo tumorigenicity of mouse lung cancer cell lines.

Further analysis provided a potential mechanism by which modulation of miR-31 expression levels could affect lung cancer cell growth: miR-31 repressed expression of the tumor-suppressor genes LATS2 and PPP2R2A. As miR-31 and these target genes were inversely expressed in human lung cancers, the authors conclude that their data has clinical relevance and that miR-31 promotes lung cancer by repressing expression of specific tumor suppressors.

Source: http://www.sciencedaily.com

 

 

TIP30 Inhibits Lung Cancer Metastasis, Study Suggests. Researchers in Shanghai, China suggest that TIP30 prevents metastatic progression of lung cancer.


Researchers in Shanghai, China suggest that TIP30 prevents metastatic progression of lung cancer.

They report these findings in the May 2009 issue of The American Journal of Pathology.

TIP30 is a putative tumor suppressor with decreased expression in numerous cancers including melanoma, breast cancer, and colon cancer. Lung cancer is the most common cancer worldwide, both in terms of incidence and of mortality.

To determine if TIP30 plays a role in lung cancer progression and metastasis, Tong et al examined TIP30 expression in paired cancerous and non-cancerous lung tissue. TIP30 expression was decreased in a third of non-small cell lung cancers compared with normal controls, and reduced TIP30 expression correlated with lymph node metastasis. In addition, inhibition of TIP30 expression promoted lung cancer metastasis and angiogenesis in mice,

Tong et al conclude that “TIP30 may function as a tumor suppressor gene and play important roles in suppressing the progression and metastasis of lung cancer.” These findings highlight TIP30 as a potential new therapeutic for metastatic lung cancer.

They report these findings in the May 2009 issue of The American Journal of Pathology.

TIP30 is a putative tumor suppressor with decreased expression in numerous cancers including melanoma, breast cancer, and colon cancer. Lung cancer is the most common cancer worldwide, both in terms of incidence and of mortality.

To determine if TIP30 plays a role in lung cancer progression and metastasis, Tong et al examined TIP30 expression in paired cancerous and non-cancerous lung tissue. TIP30 expression was decreased in a third of non-small cell lung cancers compared with normal controls, and reduced TIP30 expression correlated with lymph node metastasis. In addition, inhibition of TIP30 expression promoted lung cancer metastasis and angiogenesis in mice,

Tong et al conclude that “TIP30 may function as a tumor suppressor gene and play important roles in suppressing the progression and metastasis of lung cancer.” These findings highlight TIP30 as a potential new therapeutic for metastatic lung cancer.

Source: http://www.sciencedaily.com

 

Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges.


Summary

Research in pulmonary drug delivery has focused mainly on new particle or device technologies to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although substantial progress has been made in this respect, no significant advances have been made that would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some pathophysiological disorders that could benefit from better control of the processes after aerosol deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.

PIIS2213260013700729.gr5.lrg

Conclusions

Since the introduction of the first metered dose inhalers to the market in 1956,88 pulmonary drug delivery has made substantial progress, even leading to the first introduction of an inhalation form of insulin (Exubera) to the market. However, since the withdrawal of Exubera from the market in 2007, the field of advanced pulmonary drug delivery, other than delivery of anti-asthma and bronchodilating drugs, has stagnated. Until now the main focus of research and development efforts has been on generation of better aerosols by engineering more sophisticated particles or devices. However, optimised aerosol deposition is a necessary, but not sufficient component of pulmonary drug delivery. To overcome the biopharmaceutical challenges associated with absorption across the alveolar epithelium, control of particle clearance and targeting of specific regions or cells within the lungs requires a thorough understanding of the processes occurring at the cellular and non-cellular elements of the air—blood—barrier after aerosol drug deposition.

To achieve these goals, advanced in-vitro models, preferentially based on human cells and tissues, will be important. Furthermore, nanotechnology might contribute to the development of aerosol drug carriers, and might be necessary for the success of pulmonary drug delivery in the future.

Source: Lancet

 

 

 

 

Gastrobronchial fistula.


A 67-year-old man presented with left anterior chest pain of sudden onset. On admission, chest radiography showed left lower lobe infiltrates.

PIIS0140673607617462.fx1.lrg

8 days later, chest radiography showed a cavitating lesion, consistent with a pulmonary abscess. CT of the chest revealed a pulmonary abscess in the left lower lobe. Suspecting an oesophagobronchial fistula, we did a barium contrast study, which showed a passage from the gastric fundus to the pulmonary abscess (figure). Oesophagogastroduodenoscopy confirmed the presence of a fistula in the gastric fundus; gastric contents were seen to enter the fistula. The fistula, and the left lower lobe to which it was adherent, were surgically resected, and the diaphragm was repaired. The patient’s recovery was uneventful.

Source: Lancet

Targeting of Low-Dose CT Screening According to the Risk of Lung-Cancer Death.


BACKGROUND

In the National Lung Screening Trial (NLST), screening with low-dose computed tomography (CT) resulted in a 20% reduction in lung-cancer mortality among participants between the ages of 55 and 74 years with a minimum of 30 pack-years of smoking and no more than 15 years since quitting. It is not known whether the benefits and potential harms of such screening vary according to lung-cancer risk.

METHODS

We assessed the variation in efficacy, the number of false positive results, and the number of lung-cancer deaths prevented among 26,604 participants in the NLST who underwent low-dose CT screening, as compared with the 26,554 participants who underwent chest radiography, according to the quintile of 5-year risk of lung-cancer death (ranging from 0.15 to 0.55% in the lowest-risk group [quintile 1] to more than 2.00% in the highest-risk group [quintile 5]).

RESULTS

The number of lung-cancer deaths per 10,000 person-years that were prevented in the CT-screening group, as compared with the radiography group, increased according to risk quintile (0.2 in quintile 1, 3.5 in quintile 2, 5.1 in quintile 3, 11.0 in quintile 4, and 12.0 in quintile 5; P=0.01 for trend). Across risk quintiles, there were significant decreasing trends in the number of participants with false positive results per screening-prevented lung-cancer death (1648 in quintile 1, 181 in quintile 2, 147 in quintile 3, 64 in quintile 4, and 65 in quintile 5). The 60% of participants at highest risk for lung-cancer death (quintiles 3 through 5) accounted for 88% of the screening-prevented lung-cancer deaths and for 64% of participants with false positive results. The 20% of participants at lowest risk (quintile 1) accounted for only 1% of prevented lung-cancer deaths.

CONCLUSIONS

Screening with low-dose CT prevented the greatest number of deaths from lung cancer among participants who were at highest risk and prevented very few deaths among those at lowest risk. These findings provide empirical support for risk-based targeting of smokers for such screening.

Source: NEJM

Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges.


Research in pulmonary drug delivery has focused mainly on new particle or device technologies to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although substantial progress has been made in this respect, no significant advances have been made that would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some pathophysiological disorders that could benefit from better control of the processes after aerosol deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.
Source: Lancet