How PARPi really works

Transcription–replication conflicts underlie sensitivity to PARP inhibitors

https://www.nature.com/articles/s41586-024-07217-2

It is interesting to note that treatment of disease may become commonplace without any real understanding of how it works. One such example is the use of PARP inhibitors for the treatment of ovarian cancer due to defective DNA repair, which includes about 80% of all ovarian cancer.

Previously, through a mechanism known as synthetic lethality, it was thought that PARPi worked by trapping the PARP enzyme on the chromosome and preventing its repair activity. 

This basic research using yeast cells has demonstrated that the effect of PARPi is to alter proteins essential for DNA repair. These proteins have the memorable names of TIMELESS and TIPIN. 

Understanding of the true reason for PARPi effectiveness will enable further drug development and also explain why, for about 20% of women with ovarian cancer, PARPi treatment is of no value.

Better use for MRI

What makes small ovarian lesions light up like a lightbulb?

https://tinyurl.com/mrv6nc6b

Survival for patients with ovarian cancer is mostly determined by the complete removal of the primary tumour at the time of the initial surgery. For this to occur the extent of disease needs to be determined as effectively as possible.

This study advocates the use of diffusion weighted MRI (DWI), to show small metastases close to bowel loops. DWI plots the distribution of hydrogen atoms and measures the change in motion of these when captured in a metastasis.

Using DWI, after proper bowel preparation to overcome signal artefact, has been shown to clearly lesions measuring 4mm. or more. Using the imaging it is possible to assess the likelihood of complete clearance with an accuracy of 90%.

Using the Biobank

Sarcopenia-related Traits, Body Mass Index and Ovarian Cancer Risk: Investigation of Causal Relationships Through Multivariable Mendelian Randomization Analyses

https://tinyurl.com/bddp8hnk

One of the more important changes to medical research has been the start of the UK Biobank. Established in 2015 and now with over 500,000 participants, these volunteers have provided genetic information with full genotyping and general information about health and well-being. On-going data entry is available showing the course of disease in this large group.

This study correlates the development of ovarian cancer with BMI and strength testing together with genetic risk. Obviously with the incidence of ovarian cancer being 7/100,000 each year, the numbers are still small.

However, the early results show that the most significant strength test is the walking speed, (the faster the better), and that BMI in the overweight range is protective. As time passes more information will be obtained from the Biobank. We should all be grateful to those who joined the project.

Why stress is bad

Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment

https://tinyurl.com/mrx83sht

Stress is a known contributor to shorter survival after cancer treatment. Reasons for this have been unclear. Now, recent research using a mouse model has identified a possible mechanism by which this occurs.

All cancer patients face increased stress either through anxiety about outcomes or associated problems, such as loss of income and mobility. This stress activates the hypothalamic-pituitary-adrenal pathway with consequent increase in circulating steroid hormones.

An elevated neutrophil/lymphocyte ratio in circulating blood plasma is one of the physiological effects of stress. The neutrophils normally act to form traps for extracellular pathogens such as bacteria. A similar process will trap cancer cells, with implantation at remote sites and consequent metastasis.

Knowing the importance of stress will enable early intervention to mitigate the effect.

Dementia and Cancer

Exploring the association between cancer and cognitive impairment in the Australian Imaging Biomarkers and Lifestyle (AIBL) study

http://tinyurl.com/3n99bfnf

Previous anecdotal experience has suggested that cancer may be protective against cognitive impairment, with a lower incidence of dementia. Similarly, patients who have been diagnosed with Alzheimer’s (AD) have a lower incidence of cancer. 

This Australian study uses information from the Australian Imaging Biomarkers and Lifestyle study, (AIBL), which is an on-going measurement of the development of cognitive impairment. As part of the standard data set, those members of the study who developed cancer were compared to the others.

Even when allowing for the small numbers (546); being about one quarter of the total AIBL participants, there is a definite trend, with less AD in the cancer group. The incidence of mild cognitive decline is similar for the cancer and non-cancer group.

Other interesting findings include the rate of cognitive decline which is less for patients with cancer. In addition, those people who showed mild cognitive impairment on initial testing were less likely to progress to AD if they had cancer.