Mois : juillet 2024

Scientists have found a small molecule that turns an anti-apoptotic protein into a pro-apoptotic one, protecting against deadly metastases in a mouse model of human triple-negative breast cancer and, potentially, in other cancers [1].

Small but mighty

With cutting-edge cancer treatments now including things like antibodies and genetically engineered T-cells, small molecules seem to have fallen out of fashion. However, they can still pack a punch, if you find the right one (for instance, recently, a small molecule was discovered that extends telomeres). In this new study, researchers from Oregon State University have reported on a novel small molecule that can modify a protein ubiquitous in some cancer cells, turning it from a foe into an ally.

The protein, Bcl-2, prevents apoptosis (cellular death) in cancer cells, protecting them from intracellular self-destruction programs. Bcl-2 plays a role in many types of cancer. Previous research has discovered molecules that effectively modulate Bcl-2 in lymphomas, but solid tumors proved to be a harder target.

The cellular turncoat

In this study, the researchers started with triple-negative breast cancer, a subtype that lacks the three receptors commonly expressed in breast cancer and is considered particularly dangerous. Using modern methods of high-throughput screening, they were able to test a lot of molecules in vitro, in cancerous cells, assessing the effect on viability.

The leading compound, BFC1108, potently reduced the viability of several types of cancer cells in a dose-dependent manner. Bcl-2 knockdown cells were resistant to the treatment, showing that the molecule indeed worked on this specific protein.

The researchers then established that the reduced viability was due to increased apoptosis. Interestingly, the more Bcl-2 that cells expressed, the more vulnerable they were to apoptosis. As the team hoped, the new molecule did actually turn Bcl-2 from anti-apoptotic to pro-apoptotic, instead of just deactivating it, so more Bcl-2 means a stronger apoptotic impact.

“Cancer cells are so smart, they figure out ways to survive,” said Siva Kolluri, professor of environmental and molecular toxicology in the College of Agricultural Sciences, and the lead author on the paper. “Many therapies do work for a while, but it’s like making a car stop only to have the car move again. Here, we’re completely taking the wheels off the car. We used the same Bcl-2 pathway but fundamentally made a new discovery: changing how this protein functions so it starts killing cancer cells.”

Metastasis prevention

In vivo, BFC1108 strongly inhibited the growth of tumors in mice after they were inoculated with human breast cancer cells. Staining for apoptosis proteins revealed greatly increased apoptotic activity.

While science has made great strides against non-metastatic cancers, it struggles with metastatic ones. In triple-negative breast cancer, survival rates are about 90% for patients with localized tumors, but drop to just 12% for metastatic tumors. This holds true for many other cancers.

The researchers were thrilled to find that BFC1108 was effective against metastatic tumors as well. In a mouse model of metastatic triple-negative breast cancer, the study group had almost no metastases in the lungs (the organ that breast cancer usually metastasizes to). Importantly, the treated mice did not lose weight in the process.

“This is very promising because many metastatic cancers have high Bcl-2 levels,” said Christiane Löhr, professor of anatomic pathology in the Carlson College of Veterinary Medicine and a co-author of the paper. “This increased Bcl-2 expression is also common in cancer that has become resistant to therapies.”

Bcl-2 is also associated with liver metastasis in colorectal cancer, lymphovascular invasion of breast cancer cells, and nodal metastasis and invasion in laryngeal squamous cell carcinoma [2]. This makes BFC1108 a potential game changer for many cancer patients with bad prognoses.

“Changing the conformation of Bcl-2 and using that pathway to kill cells is a distinctively different approach than has been tried before.”, Löhr said. “Altering the function of a protein in a live cell is pretty amazing and the potential to attack cancers that have escaped other treatments, while leaving normal cells intact, is there.”

In this study, we identified BFC1108, a small molecule Bcl-2 functional converter, that suppresses primary and metastatic breast cancers in mouse xenograft models. Bcl-2 and its family members are prime molecular targets for developing new cancer therapeutics. There have been several efforts in the development of Bcl-2 inhibitors for solid cancers, but not with very encouraging results in clinical trials. Our study provides a proof of concept for the therapeutic targeting of Bcl-2 through the use of small molecules that induce the Bcl-2 killer conformation.

Literature

[1] Kopparapu, P. R., Pearce, M. C., Löhr, C. V., Duong, C., Jang, H. S., Tyavanagimatt, S., … & Kolluri, S. K. (2024). Identification and characterization of a small molecule Bcl-2 Functional Converter. Cancer Research Communications, 4(3), 634-644.

[2] Um, H. D. (2016). Bcl-2 family proteins as regulators of cancer cell invasion and metastasis: a review focusing on mitochondrial respiration and reactive oxygen species. Oncotarget, 7(5), 5193.

Revealing their findings in Aging Cell, researchers have found a new biochemical target for chronic obstructive pulmonary disease (COPD).

Smoking is only one cause

COPD, which is characterized by bouts of lung problems, has only limited treatments, is progressive and currently incurable, and often occurs in people over 60 [1]. While smoking is its most widely known risk factor, aging and environmental pollutants also contribute to the disease, and its incidence is on the rise [2]. While it has similarities to idiopathic pulmonary fibrosis (IPF), which these researchers also included in this study, the physical causes of COPD are well documented but in IPF are less clear.

However, understanding the physical causes is not the same as understanding the biochemical ones. To better grasp those, these researchers employed genome-wide association studies (GWAS), a technology that is constantly improving. They looked across the map of gene transcription and proteins for potential mechanisms and targets.

One key metric they examined was leukocyte telomere length (LTL), a biomarker of telomere attrition, one of the hallmarks of aging. Previous work has found that LTL is causally associated with IPF but not COPD [3].

Bringing together large databases

These researchers employed multiple databases containing extensive biological data. including the gene expression databases eQTLGen and GTEx, two separate proteomics databases with thousands of proteins and tens of thousands of participants, and the well-known UK Biobank along with the similar FinnGen.

Comparing their genomics databases to patient data, the researchers found a total of 16 proteins that were associated in some way with IPF, 6 proteins associated with COPD, and 17 proteins associated with LTL. While the researchers found other promising targets, only one of these proteins, SCARF2, was negatively associated with both COPD and IPF, completely independently of LTL, and these researchers’ algorithms found this to be causal: that is, higher SCARF2 is likely to protect against these lung diseases.

Other data supported this view. SCARF2 was found to be associated with gene variants that have effects on the lungs. Similarly, as expected, epithelial cells in the lungs of people with COPD had less SCARF2 than in people without it.

These results were also bolstered by similar gene expression data and multivariable analysis. Similar to the protein data, gene expression databases found that cells that expressed more SCARF2 in their mRNA were less likely to be from people with IPF or COPD. Even after adjusting for LTL, SCARF2 was still found to have a significant effect.

This protein has not been heavily investigated. Previous work has found that it is a scavenger protein that binds to acetylated low-density lipoprotein (LDL) [4]; this is widely known as the harmful form of cholesterol, although it is unclear if that relationship plays any role in COPD or IPF. Being that this is a novel and unexplored target, there are as of yet no prospective drugs for increasing SCARF2 in lung cells. If one can be found and successfully tested, this discovery might offer new hope to older people whose lungs are deteiorating from these crippling and dangerous diseases.

Literature

[1] Bhatt, S. P., Agusti, A., Bafadhel, M., Christenson, S. A., Bon, J., Donaldson, G. C., … & Martinez, F. J. (2023). Phenotypes, Etiotypes, and Endotypes of Exacerbations of Chronic Obstructive Pulmonary Disease. American Journal of Respiratory and Critical Care Medicine, 208(10), 1026-1041.

[2] Singla, A., Reuter, S., Taube, C., Peters, M., & Peters, K. (2023). The molecular mechanisms of remodeling in asthma, COPD and IPF with a special emphasis on the complex role of Wnt5A. Inflammation Research, 72(3), 577-588.

[3] Duckworth, A., Gibbons, M. A., Allen, R. J., Almond, H., Beaumont, R. N., Wood, A. R., … & Scotton, C. J. (2021). Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study. The Lancet Respiratory Medicine, 9(3), 285-294.

[4] Ishii, J., Adachi, H., Aoki, J., Koizumi, H., Tomita, S., Suzuki, T., … & Arai, H. (2002). SREC-II, a new member of the scavenger receptor type F family, trans-interacts with SREC-I through its extracellular domain. Journal of Biological Chemistry, 277(42), 39696-39702.

A recent paper in the European Journal of Epidemiology reported that recurrent miscarriage and stillbirths are associated with the occurrence of dementia, but there was insufficient evidence to establish such a connection between infertility and dementia [1].

Sex-specific differences in dementia risk

Dementia affects women more frequently than men. The authors of this paper discuss data from 2019 that shows that dementia was estimated to be responsible for one million deaths among women. In the case of men, the estimate is about half the number, at 600,000 deaths. Women also lose more years of life to dementia-related disability than men (17.7 million vs 10.6 million). Females’ long lifespans cannot explain these discrepancies fully [2, 3].

The authors believe that sex-specific dementia risk factors require investigation since well-known risk factors, such as lower education, smoking, diabetes, hypertension, depression, and pre-existing stroke, do not explain the higher magnitude of this problem among women [4].

Some studies have already addressed this issue and investigated a number of female-specific possible risk factors, suggesting that later age at menarche (first period), being nulliparous (a female who has never given birth), and premature and early menopause are dementia risk factors [5, 6]. However, as the authors point out, there has not been enough investigation into infertility and pregnancy loss (i.e., miscarriage and stillbirth) and their link to dementia.

Pregnancy loss and dementia association

For the analysis, the authors used data from 291,055 women with a median age of 55.0. Study participants were followed up for a median of 13.0 years. After the follow-up time, 3334 (1.2%) of these women developed dementia. The median age of developing the disease was 75.0. In the studied cohort, 17.9% had experienced infertility, 25.4% had experienced miscarriage, and 3.2% had experienced stillbirth.

According to the analyzed data, “there was insufficient evidence to establish an association between infertility and dementia.” However, the analysis indicated that recurrent miscarriage (three or more) leads to a “modestly higher risk of dementia” when compared to women who didn’t experience a miscarriage, and women who experienced recurrent (two or more) stillbirths also had a 1.64-fold increased dementia risk when compared to women who didn’t experience it. This effect size (1.64) is similar in size to the effect size of conditions such as obesity (1.6), hypertension (1.6), and diabetes (1.5) [4], which makes it an important risk factor.

Scarce research on the topic

The authors of current papers reviewed previous research on this topic, noting there were not many studies that addressed the relationship between stillbirths, miscarriages, infertility, and dementia risk.

In fact, the association between infertility and dementia was addressed by only one cohort study. The authors of that study observed a lower risk of dementia among women with secondary infertility [7]. One of the differences between that study and this one is that in this study, a much higher fraction of women was considered infertile (17.9% as opposed to 2.4% in the previous study). The difference stems from a different way of identifying infertile women, as that previous study didn’t include women who didn’t seek medical help for infertility, and this study had much broader inclusion criteria.

Regarding the link between recurrent miscarriages and dementia, the authors point to three previous studies that investigated it. They “found no evidence on the association between miscarriage (single or recurrent) and dementia” [7-9]. That is contradictory to this study, which reported a modest association between recurrent miscarriages, defined as three or more miscarriages, and dementia. The authors point to the lack of consensus regarding the definition of recurrent miscarriages, which makes a difference in the data analysis. The previous studies only distinguished between zero, one, or more than two miscarriages. They didn’t have a separate category for three or more miscarriages, as this study did (and where the association was observed).

Only two previous studies investigated the link between recurrent stillbirths and dementia, with inconsistent results. One reported the association, while the second didn’t [8, 9]. The authors point out that both studies have serious limitations, such as a short follow-up period to a median age of 49 and inadequate control for confounding factors. Those limitations were addressed in this study, which reported increased dementia risk for women with recurrent stillbirths.

Possible molecular mechanisms

Based on other observational studies, the authors hypothesized about possible underlying molecular processes. One of them is the role of oestrogen and progesterone, two hormones that play crucial roles in many female reproduction-related processes. They are also essential regulators of neuroplasticity [10]. The researchers note that “women with pregnancy loss may have inadequate levels of oestrogen or progesterone.” Such deficiencies can be the reason for declining neuroplasticity and dementia development.

They also note the possible impact on dementia development caused by molecular changes that result from stroke, diabetes, and depression, conditions more common among women who experience pregnancy loss [11-13]. However, studies are necessary to confirm those hypotheses.

Limitations of the study

As with every study, this one had some limitations, including data acquisition: the questionnaires might have introduced recall bias. Also, due to the nature of the data, the researchers were unable to distinguish whether infertility was due to her body or that of her male partner. They also didn’t have data regarding some factors that might influence the results, such as smoking, alcohol intake, BMI, hormonal or blood biomarkers, and missing dementia cases (as they might have been unidentified at the time). Additionally, the authors didn’t investigate different subtypes of dementia. The results have limited generalizability since the women included in the study were mostly Caucasian.

Literature

[1] Liang, C., Dobson, A. J., Chung, H. F., van der Schouw, Y. T., Sandin, S., Weiderpass, E., & Mishra, G. D. (2024). Association of infertility and recurrent pregnancy loss with the risk of dementia. European journal of epidemiology, 10.1007/s10654-024-01135-3. Advance online publication

[2] World Health Organization. Global health estimates: leading cause of death, cause specific mortality, 2000–2019.

[3] World Health Organization. Global health estimates: leading causes of DALYs disease burden, 2000–2019.

[4] Livingston, G., Huntley, J., Sommerlad, A., Ames, D., Ballard, C., Banerjee, S., Brayne, C., Burns, A., Cohen-Mansfield, J., Cooper, C., Costafreda, S. G., Dias, A., Fox, N., Gitlin, L. N., Howard, R., Kales, H. C., Kivimäki, M., Larson, E. B., Ogunniyi, A., Orgeta, V., … Mukadam, N. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet (London, England), 396(10248), 413–446.

[5] Gilsanz, P., Lee, C., Corrada, M. M., Kawas, C. H., Quesenberry, C. P., Jr, & Whitmer, R. A. (2019). Reproductive period and risk of dementia in a diverse cohort of health care members. Neurology, 92(17), e2005–e2014.

[6] Fu, C., Hao, W., Ma, Y., Shrestha, N., Virani, S. S., Mishra, S. R., & Zhu, D. (2023). Number of Live Births, Age at the Time of Having a Child, Span of Births and Risk of Dementia: A Population-Based Cohort Study of 253,611 U.K. Women. Journal of women’s health (2002), 32(6), 680–692.

[7] Andolf, E., Bladh, M., Möller, L., & Sydsjö, G. (2020). Prior placental bed disorders and later dementia: a retrospective Swedish register-based cohort study. BJOG : an international journal of obstetrics and gynaecology, 127(9), 1090–1099.

[8] Basit, S., Wohlfahrt, J., & Boyd, H. A. (2019). Pregnancy loss and risk of later dementia: A nationwide cohort study, Denmark, 1977-2017. Alzheimer’s & dementia (New York, N. Y.), 5, 146–153.

[9] Gong, J., Harris, K., Peters, S. A. E., & Woodward, M. (2022). Reproductive factors and the risk of incident dementia: A cohort study of UK Biobank participants. PLoS medicine, 19(4), e1003955.

[10] Yagi, S., & Galea, L. A. M. (2019). Sex differences in hippocampal cognition and neurogenesis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 44(1), 200–213.

[11] Liang, C., Chung, H. F., Dobson, A. J., Hayashi, K., van der Schouw, Y. T., Kuh, D., Hardy, R., Derby, C. A., El Khoudary, S. R., Janssen, I., Sandin, S., Weiderpass, E., & Mishra, G. D. (2022). Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women. BMJ (Clinical research ed.), 377, e070603.

[12] Kolte, A. M., Olsen, L. R., Mikkelsen, E. M., Christiansen, O. B., & Nielsen, H. S. (2015). Depression and emotional stress is highly prevalent among women with recurrent pregnancy loss. Human reproduction (Oxford, England), 30(4), 777–782.

[13] Biessels, G. J., Staekenborg, S., Brunner, E., Brayne, C., & Scheltens, P. (2006). Risk of dementia in diabetes mellitus: a systematic review. The Lancet. Neurology, 5(1), 64–74.