Adam Davidson, CEO of Trident Royalties, discusses offtake milestones and catalysts to boost FY24. Watch the video here.
Olaparib-Resistant BRCA2 Ovarian Cancer Cells with Restored BRCA2 Abrogate Olaparib-Induced DNA Damage and G2/M Arrest Controlled by the ATR/CHK1 Pathway for Survival:
https://www.mdpi.com/2073-4409/12/7/1038
"At sublethal doses of inhibitors for olaparib-sensitive cells, combination treatments exerted promising synergistic antitumor effects on PEO1-OR cells. Moreover, co-treatment with ATR/CHK1 inhibitors and olaparib induced a synergistic decrease in cell viability and survival and increase in DNA damage in the cell models examined, most notably in olaparib-sensitive cells. These findings support the potential utility of combinations of inhibitors of the ATR/CHK1 pathway together with olaparib in avoiding or overcoming drug resistance of OC."
ATB
Replicative stress in gastroesophageal adenocarcinoma is associated with chromosomal instability and sensitivity to DNA damage response inhibitors:
https://www.biorxiv.org/content/10.1101/2023.03.27.534412v1
Direct .pdf: https://www.biorxiv.org/content/10.1101/2023.03.27.534412v1.full.pdf
“In line with these results in patients, we found that TP53 mutation, ploidy abnormalities, and H2AX expression independently positively correlate with sensitivity to Chk1/2 and Wee1/2 DDR pathway inhibitors in gastric cancer cell models. The predictive power for DDR pathway sensitivity was improved when these parameters of aneuploidy and DDR were combined. These findings suggest that ploidy abnormalities and H2AX expression may have clinical value as biomarkers to predict response to DDR pathway inhibitors (Chk1/2 and Wee1) in patients with gastric and esophageal adenocarcinoma.”
NOTE -
"We used prexasertib and MK 1775 as potent inhibitors of chk1/2 and Wee1, respectively, as these DDR inhibitors are commonly used in clinical trials for solid tumors. There are however next-generation DDR inhibitors that may prove less toxic and more efficacious; our results can therefore be used as a proof-of-concept."
ATB
1. Acrivon: Precision-Testing Your Trial Patients Before Enrolment:
https://seekingalpha.com/article/4590196-acrivon-precision-testing-trial-patients
2. http://www.accro.com.cn/en/about_en.html
"In addition, AC-201, a selective TYK2/JAK1 inhibitor with huge potential for treating inflammatory and autoimmune diseases, is in IND filing stage in Australia. The company has multiple compounds in the PCC and preclinical research and development stages. Accro Bioscience owns global rights of all its assets with more than 10 patents issued in China, Japan, Korea, US and EU, etc.
The Company is headquartered in the BioBAY of Suzhou Industrial Park."
3. TYK2 single-nucleotide variants associated with the severity of COVID-19 disease:
https://pubmed.ncbi.nlm.nih.gov/36959416/
"The results of this study suggest that TYK2 SNPs might be utilized to identify individuals who are at risk for severe COVID-19, in order to better manage their health care. It is predicted that the presence of some alleles (T in rs2304255, A in rs12720354, and G in rs12720207) of TYK2 can affect COVID-19 severity by reducing TYK2 expression and thereby affecting the regulatory role of TYK2 in the immune response."
ATB
https://www.businesswire.com/news/home/20230315005006/en/Boundless-Bio-Announces-Upcoming-Presentation-at-the-American-Association-for-Cancer-Research-Annual-Meeting-2023
https://boundlessbio.com/what-we-do
ATB
Keep banging that drum ;)
https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.16415
"Chk1 has been of interest as a target for anticancer drug development for a considerable time, and a number of selective Chk1 inhibitor drugs have been developed, some of which are currently in clinical trials [[11]]. Importantly, low concentrations of two Chk1 inhibitors, CCT244747 and PF477736, were able to rescue zygotic arrest of murine oocytes induced to express exogenous mutant Chk1 [[5, 6]], with apparently normal expression of key developmental genes and global genomic transcriptional changes in the developing blastocysts. Astonishingly, implantation of such “rescued” murine blastocysts into recipient mice resulted in the birth of normal healthy pups at the expected frequency, indicating that in mice at least if the initial Chk1-induced zygotic arrest can be overcome, subsequent development can proceed normally. Not only that, but these mice reached adulthood without any sign of pathology and exhibited normal fertility [[5, 6]].
Chk1 inhibitor treatment also enabled human zygotes expressing endogenous mutant Chk1 to overcome zygotic arrest in?vitro and progress to blastocysts which exhibited normal expression of critical developmental genes. Although the issue of whether such “rescued” human blastocysts, like their murine counterparts, would retain full developmental potential has not yet been tested, pluripotent stem cell lines with normal characteristics were developed from some of the “rescued” blastocysts [[6]]. Thus, these findings offer hope that Chk1 inhibitor treatments might offer a pharmacological solution to IVF failure in females suffering from infertility caused by inherited Chk1 mutations."
ATB
One for the dedicated followers of science....
https://www.biorxiv.org/content/10.1101/2023.03.11.532189v1
full .pdf: https://www.biorxiv.org/content/biorxiv/early/2023/03/11/2023.03.11.532189.full.pdf
"Thus, our study suggests that co-treatment of platinum-based chemotherapies with CHK1 inhibitors, which restore SSBP1 localization to the mitochondria and increase ROS, may be an approach to overcome platinum resistance. Moreover, they suggest a general mechanism of resistance for therapeutic agents whose cytotoxicity is mediated in part by increasing the steady-state levels of nuclear H2 O2 and is in accordance with the growing body of evidence that mitochondrial function
is a critical determinant of therapeutic response"
ATB
https://www.biospace.com/article/releases/allorion-therapeutics-a-next-generation-precision-medicine-company-focusing-on-oncology-and-autoimmune-diseases-raises-50-million-series-b-financing/
"Allorion has advanced two small molecules to the IND stage. ARTS-011, whose IND has been filed in China in recently, is an allosteric inhibitor targeting the TYK2 pseudokinase domain used to treat autoimmune diseases such as psoriasis and lupus. ARTS-021, with its IND to be filed in the U.S. and China shortly, is a highly potent CDK2 isoform selective inhibitor for treatment of solid tumors such as ovarian, endometrial, and breast cancer. There are three additional projects nearing the preclinical candidate stage, including an isoform selective inhibitor, an allosteric inhibitor, and a first-in-class molecule targeting a novel synthetic lethal partner of an undruggable mutation. Pre-clinical development of these drug candidates will begin in 2023, and IND will be submitted in China and the U.S."
ATB
Among the duplicitous dross posted and floating about we still have some decent info shared by the good folk here, thank you for sticking around!
1.
Maximizing TechBio Deal Potential: Platform vs. Asset Deals:
Nothing Earth-shattering, but a concise coffee time read & pertinent to Sareum's situation:
https://www.nfx.com/post/techbio-deal-potential
2.
Studying hallmarks of cancer :
A relatively short piece worthy of ones time, especially as a newcomer to this arena..
Your guide to core hallmarks of cancer and emerging hallmarks and enabling characteristics:
https://www.abcam.com/cancer/studying-hallmarks-of-cancer
ATB
...and impaired 53BP1 recruitment, and cellular senescence
https://www.nature.com/articles/s41556-023-01096-x
ATB
Ah yes, JAK1 inhibition... as we know, deucravacitinib flunked in Ulcerative Colitis trials.
https://www.dovepress.com/clinical-evaluation-of-upadacitinib-in-the-treatment-of-adults-with-mo-peer-reviewed-fulltext-article-CEG#
ATB
1.
Overcoming PARP inhibitor resistance in
ovarian cancer
:
https://ijgc.bmj.com/content/33/3/364
Direct .pdf: https://ijgc.bmj.com/content/ijgc/33/3/364.full.pdf
"Modulating the cell cycle checkpoint signaling in OC with agents targeting DDR pathways (ATR-CHK1-WEE1 pathway) is an exciting option with mechanistic rationale for the combination with PARPi or cytotoxic chemotherapy as they have the potential to induce synthetic lethality. All these combinations require comprehensive pre-clinical data to assess schedule timing of dosing for optimal strategy combination and to limit the induced hematological toxicities."
2.
Venetoclax-Resistant T-ALL Cells Display Distinct Cancer Stem Cell Signatures and Enrichment of Cytokine Signaling:
https://www.mdpi.com/1422-0067/24/5/5004
"Collectively, our data suggest that venetoclax resistance can be mediated through the enrichment of distinct gene signatures and cytokine signaling pathways."
ATB
A Study to Evaluate Effectiveness and Safety of BMS-986322 in Participants With Moderate-to-Severe Psoriasis:
https://www.clinicaltrials.gov/ct2/show/NCT05730725
ATB
https://www.mdpi.com/1422-0067/24/4/3391
SAR-20347 gets a mention...
Also, Acrivon pushing on with their CHK1i:
Acrivon Therapeutics to Participate on a Panel at Cowen's 43rd Annual Health Care Conference:
CEO to participate on ovarian cancer panel and will highlight ACR-368, a DNA Damage Response (DDR) inhibitor in clinical testing for platinum-resistant advanced ovarian cancer and other solid tumors....
https://www.barrons.com/amp/articles/acrivon-therapeutics-to-participate-on-a-panel-at-cowen-s-43rd-annual-health-care-conference-dfe94f20
ATB
Another science heavy piece for those who might be interested:
https://www.mdpi.com/2079-7737/12/3/376
"Single or combinatory inhibitions were simulated mimicking therapeutic interventions, and output patterns were analyzed to interpret changes in polarization and cell function. Results: We show that inhibiting a single target is inadequate to modify an established polarization, and that in combination therapy, inhibiting numerous targets with individually small effects is frequently required. Our findings show the importance of JAK1, JAK3 and STAT6, and to a lesser extent STK4, Sp1 and Tyk2, in establishing an M1-like pro-inflammatory polarization, and NFAT5 in creating an anti-inflammatory M2-like phenotype. Conclusions: Here, we demonstrate a protein–protein interaction (PPI) network modeling the intracellular signalization driving macrophage polarization, offering the possibility of therapeutic repolarization and demonstrating evidence for multi-target methods."
ATB
For the science folk :)
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00053-1/fulltext?rss=yes
direct .pdf https://www.thelancet.com/action/showPdf?pii=S2352-3964%2823%2900053-1
ATB
- (RINVOQ®) for the Treatment of Adults with Moderate to Severe Crohn's Disease:
https://news.abbvie.com/article_display.cfm?article_id=12560
A refresher:
Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations:
https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-019-1964-1
Here's to a positive week ;)
ATB
Paris center reports results of mechanical ventilation, JAK-STAT inhibition for some patients:
https://www.eurekalert.org/news-releases/980264
One might postulate whether JAK inhibition could help alleviate some of the issues we are seeing throughout the western world due to the huge increase in Myocarditis/Pericarditis (to name a few ailments) since the rollout of that which cannot be criticised.
Dr John Campbell, is a superb man BTW, look him up.
Time will tell.
Off for a walk, in my tin hat.
ATB
1.
On a financially related note, the following gives a glimpse into how the use of Sotyktu is panning out in the real world, a word of caution regards the possible side effects - not to mention the monthly cost:
https://www.peoplespharmacy.com/articles/what-can-you-use-for-psoriasis-if-you-cant-afford-otezla
"Sotyktu (deucravacitinib) is a relatively new psoriasis medicine. It is in a somewhat similar category as some other biologic medications such as upadacitinib (Rinvoq) or tofacitinib (Xeljanz).
In a four-month trial of this drug to treat psoriatic arthritis, the most common side effects were sore throat, respiratory infection, sinusitis, bronchitis, rash, headache and diarrhea (Annals of the Rheumatic Diseases, June 2022). Sotyktu lowers the ability of the immune system to fight infections and must not be used in combination with other drugs that affect immune response. Some people react to this drug by developing angioedema (which can be life threatening). There are also concerns about serious infections such as tuberculosis as well as the blood cancer lymphoma.
The price might also be a worry unless your insurance plan will cover Sotyktu. GoodRx.com reports the monthly price without coverage or coupons at more than $11,000. So if you can’t afford Otezla, Sotyktu might also be out of reach."
In addition and on a completely different topic, an up to date, science heavy piece for those who like a read:
Interferon therapy and its association with depressive disorders – A review:
https://www.frontiersin.org/articles/10.3389/fimmu.2023.1048592/full
Food for thought as ever, one must keep an eye on the bigger picture.
ATB
....dealing another blow to troubled JAK inhibitor:
https://www.fiercepharma.com/pharma/galapagos-filgotinib-flops-phase-3-crohns-disease-trial-gives-eu-crohns-indication
ATB