Australia's largest stock trading and investment forum Australia's #1 stock forum

PAA

Click for more information

13.5%

21.0¢ pharmaust limited

Brilliant post AD. Best analysis ever to simplify a complex...

First 3 Last

Share
Profile

Follow
ThriftyClown

267 Posts.

355

07/05/23

22:16

Post #: 67649014
Share
Originally posted by adreamer: ↑

Research Article published 6 May 2023:
Induction of endoplasmic reticulum stress is associated with the anti-tumor activity of monepantel across cancer types

https://onlinelibrary.wiley.com/doi/10.1002/cam4.6021
(great find, Paralogical)This paper has been years in the making and is the culmination of critical, multi-disciplinary research lead from the world recognised Olivia Newton-John Cancer Research Institute.

This will underpin the direction of PharmAust into the future in relation to the treatment of a broad range of cancers in humans.

Some Key contributors:
Roger Aston (PharmAust)
Richard Molard (PharmAust) - roles included funding acquisition!!!
Walter Douglas Fairlie (Olivia Newton-John Cancer Research Institute) - LEAD
Includes interactions with WEHI & multiple research grants (note funding via PharmAust)

At first glance, it is somewhat overwhelming with scientific jargon and this is very difficult to consume.
So here is a more simplistic version of the Abstract. I am also offering some definitions for some of the terms that I don't hear used in common language too. What I can't do is understate the importance of this published works. IT clearly articulates the viability and validity of the PharmAust held IP and vision held for Monepantel.

Some key terms first:
ATF4-mediated ER stress responses - involve activating genes for protein folding, amino acid metabolism, antioxidant defence, apoptosis, and autophagy to cope with endoplasmic reticulum stress. (ok, now read the rest of the definitions and come back to this one!)
Apoptosis- cell death
Autophagy - a process that helps cells break down and recycle their components
EndoplasmicReticulum (ER) - a cellular structure involved in protein synthesis
ER stress responses - the cellular reactions triggered when the endoplasmic reticulum (ER), a specialised organelle (a sub-cellular structure that has one or more specific jobs to perform in the cell) involved in protein synthesis and folding, becomes overwhelmed or disrupted. The ER plays a crucial role in ensuring that newly synthesised proteins are correctly folded and processed before they are transported to their functional destinations within the cell.
mTOR (mechanistic target of rapamycin) - a protein kinase that plays a central role in regulating cell growth, metabolism, and survival. It acts as a key regulator of various cellular processes in response to nutrient availability, growth factors, and energy status.
Pro‐apoptotic proteins - initiate apoptosis by blocking the anti‐apoptotic activity of Bcl‐2 and Bcl‐xL by binding to their mitochondrial binding sites or by triggering the activation of pro‐apoptotic Bax/Bak.
RNA-sequencing - a technique that allows them to analyse gene activity
Western blotting -also known as immunoblotting, is a widely used laboratory technique for detecting and analysing specific proteins in a sample of biological material.
3D cultures - cultures refer to a method of growing cells in the laboratory that better mimics the natural environment of cells in the body. In traditional cell culture, cells are typically grown in a flat, two-dimensional (2D) layer on a plastic dish or flask. However, this does not fully replicate the complex three-dimensional structure and interactions between cells that occur in tissues and organs.

Now, Abstract (with less jargon):

Monepantel is a drug that can kill parasitic worms and also has the ability to fight against cancer. Scientists have been studying this drug for a while, but they still don't know exactly how it works in human cells. However, they have some clues about its effects on cell processes like the cell cycle (the process of cell growth and division), mTOR signaling (a pathway that regulates cell growth and metabolism), and autophagy (a process that helps cells break down and recycle their components).

To understand how monepantel affects cancer cells, the researchers conducted experiments using more than 20 different types of solid cancer cells. They tested the drug's ability to reduce cell viability (how well t
he cells can survive) and induce apoptosis (cell death) in a subset of these cells, including cells grown in 3D cultures. They also used genetic techniques to delete specific genes involved in apoptosis and autophagy to see how these processes contribute to the drug's effectiveness. Additionally, they performed RNA-sequencing, a technique that allows them to analyze gene activity, on four cell lines treated with monepantel, and confirmed the changes in gene expression using a method called Western blotting.The results of their experiments showed that monepantel can slow down the growth of a wide range of cancer cells. In some cases, it induced apoptosis, which they confirmed by using cells that lacked certain genes involved in apoptosis. However, even in cells where apoptosis was blocked, the drug still inhibited cell growth, indicating that it affects the cell cycle as the main way to fight cancer.

Previous studies have suggested that autophagy, another cell process, may also contribute to cell death caused by monepantel. The researchers observed autophagy induction in multiple cell lines, but when they deleted a key gene involved in autophagy, called ATG7, they found that it had minimal impact on the drug's ability to slow down cell growth.

This suggests that autophagy might be associated with the drug's effects on cancer cells, but it is not necessary for its anti-tumor activity.Further analysis of the genes in the treated cells revealed that monepantel downregulated many genes involved in the cell cycle, while upregulating genes related to a stress response in the endoplasmic reticulum (a cellular structure involved in protein synthesis). These changes were particularly associated with ATF4-mediated ER stress responses, especially genes involved in amino acid metabolism and protein synthesis.

In conclusion, based on their findings, the researchers propose that monepantel's anti-cancer activity is likely triggered by its effects on mTOR signaling, the cell cycle, and autophagy. The drug seems to disrupt the cell cycle and induce apoptosis in some cases, while autophagy may be associated with its anti-tumor effects but not necessarily required. The changes in gene expression observed suggest that monepantel affects various cellular processes related to cell growth and metabolism, providing insights into its mechanisms of action against cancer cells.

Now for a KICKER of a diagram:
Let's select a few to review:
Top, Left > No big impact on healthy cells!
Top, Middle > Again, no big impact on healthy cells
Top, Left > BOOM - absolutely huge response to MELANOMA
Middle, middle > another BOOM with OVARIAN CANCER
Lower, Left > saving the biggest BOOM for something that is incredibly hard to treat, BRAIN CANCER

NOTE: The blood/brain barrier work underway with MND is vital to brain cancer analysis.
Others are also exciting but these are my top liners above.

To say this is both exciting and affirmation of my long held belief is an understatement. Thank you to the researcher and to PharmAust for enabling this research & obtaining the grants to make it as broad and enlightening.

adreamer

Expand

Brilliant post AD.

Best analysis ever to simplify a complex scientific study. Well done on your time and effort in making this digestible on a public forum. Much appreciated.

I strongly encourage ALL readers of this excellent summary to give it a GA to get it noticed on HC home page.

We can't overstate the significance of this study and the implications for our Human cancer program.

BOOM indeed !!!
PAA Price at posting: 8.7¢ Sentiment: Buy Disclosure: Held
22 Upvote

4 Great analysis

Reply

There are more pages in this discussion • 82 more messages in this thread...

First 3 Last

Add PAA (ASX) to my watchlist

(20min delay)
Last 21.0¢		Change 0.025(13.5%)		Mkt cap ! $73.24M

Open	High	Low	Value	Volume
22.5¢	24.0¢	21.0¢	$1.254M	5.695M

Buyers (Bids)

No.	Vol.	Price($)
2	191936	21.0¢

Sellers (Offers)

Price($)	Vol.	No.
21.5¢	16289	2

View Market Depth

No.	Vol.	Price($)
5	365000	0.205
11	349378	0.200
3	125128	0.195
1	144302	0.190
4	123778	0.185

Price($)	Vol.	No.
0.210	131578	1
0.215	136343	2
0.220	127365	5
0.225	139284	4
0.230	178728	4

Last trade - 10.27am 17/05/2024 (20 minute delay)


Last 19.5¢			Change 0.025 ( 6.91 %)
Open	High		Low	Volume
23.5¢	24.0¢		19.5¢	4874703
Last updated 10.42am 17/05/2024 ?

PAA (ASX) Chart