Rapamycin Press

Discoveries on Aging for Experts and Amateurs #rapamycin co-publisher of Aging

[Rapamycin Press @RapamycinPress]

… it is more dangerous not to use anti-aging drugs than to use them … If you read this article, you will realize that the time is now

https://t.co/cSGzb3UhI4

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

Now on MedLine, PubMed and PMC !
@weldeiry

https://t.co/5ZLZiQT7ps

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

The reports of my death are greatly exaggerated.

https://t.co/IRUbaIL9UF

[Aging Journal @AgingJrnl]

"mTOR-Driven Aging and Rapamycin with Dr. Blagosklonny and Dennis Mangan" was Aging's most viewed YouTube video in 2023, with *170 hours* watched 🎥
#MyYearOnYouTube2023
https://t.co/3ZfDlZ9sAG

[Wafik S. El-Deiry, MD, PhD, FACP @weldeiry]

Pleased to share the published version of our paper👇

Transfected SARS-CoV-2 spike DNA for mammalian cell expression inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells and increases cancer cell viability after chemotherapy exposure

https://t.co/4lC6yRCF8J

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

Great paper !

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

Thank you, David! I am happy that my article is liked 🩷 I must continue living to write with you a new chapter

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

Avastin for brain tumors and metastases: Hype or Harm

Mikhail Blagosklonny, MD, PhD
Abstract:

In brain tumors and brain metastases, bevacizumab (Avastin) may decrease inflammation and edema and may be (or not) thus beneficial symptomatic. However, Avastin can decrease penetration of the MRI contrast into brain tumor, causing pseudo-response by MRI without affecting tumor real progression, thus imitating the extension of phony PFS, without increasing OS. Also, Avastin decreases penetration of chemotherapy and targeted therapy, potentially making the treatment less effective.

Pseudo-response caused by anti-VEGF agents in brain tumors and metastasis
In two large-scale, randomized, phase III trials (published in NEJM) [1], [2] treatment of Glioblastoma Multiforme (GBM) with bevacizumab (Avastin), anti-VEGF antibody, extended progression-free survival (PFS) but failed to prolong overall survival (OS).
As recently reviewed, bevacizumab (Avastin) does not cause favorable results in GBM [3].Why?
VEGFR increased vessel permeability and bevacizumab (Avastin) blocks this. Avastin decreases vessels leakage, stabilizes blood–brain barrier (BBB) and prevents penetration of the MRI contrast into the tumor. The enhancement may decrease following BBB normalization, as early as 24–48 h after initiation of therapy [4].
The size of brain tumors is measured by contrast-enhanced MRI. And Avastin may cause pseudo-response be not a true antitumor effect [5]. Tumor may become poorly visible by contrast-enhanced MRI (“nonenhancing tumor”). By restoring the blood–brain barrier (BBB), Avastin reduces T1 contrast enhancement and T2/FLAIR hyperintensity on MRI, obscuring detection of tumor progression [4].
Pseudo-response can be caused by anti-VEGFR inhibitors such as multi-kinase inhibitors such vandetanib, lenvatinib, cabozantinib and others. Vandetanib, multi-kinase inhibitor, inhibits VEGFR, restored the BBB in the tumor vasculature, resulting in loss of tumor detectability in Gd-DTPA MRI, but not USPIO-enhanced MRI scans [6], [7]. Restoration of the BBB, resulting in the inability to detect these tumors via contrast-enhanced MRI [8].
[Note: Treatment of my metastases by the CLA combo [9], including Lenvatinib (inhibits VEGFR1-3, FGFR, PDGFR) caused a dramatic and fast response observed by contrast-MRI on Oct/02/23]. [9]
Response rates, disease control of the intracranial metastases and overall survival were NOT improved by addition Avastin to chemotherapy. But, progression-free survival (PFS) and intracranial PFS (iPFS) were significantly prolonged [10]. Avastin is intended to decrease blood supply to the tumor, decreasing penetration of both contrast and drugs.

Avastin and Anti-VEGFR agents can decrease penetration of drugs in brain tumors
In treatment of brain tumors, unlike “body” tumors, Avastin (and other inhibitors of angiogenesis) may be harmful [11], [12],[3], by decreasing penetration of anti-cancer agents into the tumor.
While treatment of other tumor types may be improved by combining chemotherapy with anti-angiogenic drugs, inhibiting angiogenesis in brain tumors may antagonize the efficacy of chemotherapeutic drugs by normalizing (stabilizing) the blood-brain barrier (BBB) [13].

Numerous studies showed that anti-angiogenesis agents may induced drug resistance, especially of brain tumors [14-17] [18] [19-21]. For example, Anti-Angiogenesis agents decrease penetration of temozolomide [20], [22] and trastuzumab [16] in brain tumors. In cancer xenografts, bevacizumab causes reduced tumor uptake of trastuzumab, because of the blood flow and vascular permeability reduction [16]. In NSCLC patients, bevacizumab reduced perfusion and net influx rate of docetaxel. The effect lasted from 5 hr to 4 days after infusion of bevacizumab [19].
Vandetanib and other inhibitor of VEGF receptors, normalizes tumor vessels and alleviates edema in glioblastoma patients [23]. In brain, vessel normalization has an antagonizing effect on temozolomide. normalization of tumor blood vessels by antiangiogenic therapy may have an adverse effect on the efficacy of chemotherapeutic compounds in brain. The amount of tumor vessel leakiness, which may be deduced from radiologic imaging, may provide a clue to the dosing of antiangiogenic compounds [22]. Glioma xenografts in mice brain, cotreatment with vandetanib reduced sensitivity to temozolomide [22].
Because of a lack of survival benefit and higher toxicity, the combination of Avastin and pemetrexed cannot be recommended in advanced lung cancer. [24]
Bi-phasic response to combo containing an anti-VEGFR drug

When EGFR inhibitors and VEGFR inhibitors are used in combination, the killing of tumor cells increased in the early stage but decreased in a later stage, manifested as drug resistance [14]. The synergistic effect is transient, a narrow window of time of the beginning of treatment [15]. There is the optimal timing of combining VEGFR inhibition with EGFR inhibition [14]. In a mathematical model, anti-cancer drug should be given first and anti-VEGF drug should be taken second [25]. Ma et al suggested intermittent treatment schedules to increase chemotherapeutic drug exposure [21].
Illustration:

Verhoeff JJ et al. Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme [PubMed]
MRI Images: in patients with GBM, the impressive decreases of contrast enhancement in these tumors on anti-angiogenic treatment (Figure 1A-E) are not necessarily synonymous with anti-tumour effect. [13]
References
1. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014; 370: 709-722.
2. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014; 370: 699-708.
3. Zhang AB, Mozaffari K, Aguirre B, Li V, Kubba R, Desai NC, Wei D, Yang I, Wadehra M. Exploring the Past, Present, and Future of Anti-Angiogenic Therapy in Glioblastoma. Cancers (Basel). 2023; 15.
4. Hutterer M, Hattingen E, Palm C, Proescholdt MA, Hau P. Current standards and new concepts in MRI and PET response assessment of antiangiogenic therapies in high-grade glioma patients. Neuro Oncol. 2015; 17: 784-800.

5. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010; 28: 1963-1972.

6. Claes A, Gambarota G, Hamans B, van Tellingen O, Wesseling P, Maass C, Heerschap A, Leenders W. Magnetic resonance imaging-based detection of glial brain tumors in mice after antiangiogenic treatment. Int J Cancer. 2008; 122: 1981-1986.

7. Daldrup-Link HE, Okuhata Y, Wolfe A, Srivastav S, Oie S, Ferrara N, Cohen RL, Shames DM, Brasch RC. Decrease in tumor apparent permeability-surface area product to a MRI macromolecular contrast medium following angiogenesis inhibition with correlations to cytotoxic drug accumulation. Microcirculation. 2004; 11: 387-396.

8. Leenders WP, Kusters B, Verrijp K, Maass C, Wesseling P, Heerschap A, Ruiter D, Ryan A, de Waal R. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin Cancer Res. 2004; 10: 6222-6230.

9. Blagosklonny MV. My battle with cancer. Part 1. Oncoscience. 2024; 11: 1-14.

10. Tian Y, Zhai X, Tian H, Jing W, Zhu H, Yu J. Bevacizumab in Combination with Pemetrexed and Platinum Significantly Improved the Clinical Outcome of Patients with Advanced Adenocarcinoma NSCLC and Brain Metastases. Cancer Manag Res. 2019; 11: 10083-10092.

11. Thompson EM, Frenkel EP, Neuwelt EA. The paradoxical effect of bevacizumab in the therapy of malignant gliomas. Neurology. 2011; 76: 87-93.

12. Nguyen HS, Milbach N, Hurrell SL, Cochran E, Connelly J, Bovi JA, Schultz CJ, Mueller WM, Rand SD, Schmainda KM, LaViolette PS. Progressing Bevacizumab-Induced Diffusion Restriction Is Associated with Coagulative Necrosis Surrounded by Viable Tumor and Decreased Overall Survival in Patients with Recurrent Glioblastoma. AJNR Am J Neuroradiol. 2016; 37: 2201-2208.

13. Verhoeff JJ, van Tellingen O, Claes A, Stalpers LJ, van Linde ME, Richel DJ, Leenders WP, van Furth WR. Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme. BMC Cancer. 2009; 9: 444.

14. Liang W, Zheng Y, Zhang J, Sun X. Multiscale modeling reveals angiogenesis-induced drug resistance in brain tumors and predicts a synergistic drug combination targeting EGFR and VEGFR pathways. BMC Bioinformatics. 2019; 20: 203.

15. Huang D, Lan H, Liu F, Wang S, Chen X, Jin K, Mou X. Anti-angiogenesis or pro-angiogenesis for cancer treatment: focus on drug distribution. Int J Clin Exp Med. 2015; 8: 8369-8376.

16. Pastuskovas CV, Mundo EE, Williams SP, Nayak TK, Ho J, Ulufatu S, Clark S, Ross S, Cheng E, Parsons-Reponte K, Cain G, Van Hoy M, Majidy N, et al. Effects of anti-VEGF on pharmacokinetics, biodistribution, and tumor penetration of trastuzumab in a preclinical breast cancer model. Mol Cancer Ther. 2012; 11: 752-762.

17. Cesca M, Frapolli R, Berndt A, Scarlato V, Richter P, Kosmehl H, D'Incalci M, Ryan AJ, Giavazzi R. The effects of vandetanib on paclitaxel tumor distribution and antitumor activity in a xenograft model of human ovarian carcinoma. Neoplasia. 2009; 11: 1155-1164.

18. Bello E, Taraboletti G, Colella G, Zucchetti M, Forestieri D, Licandro SA, Berndt A, Richter P, D'Incalci M, Cavalletti E, Giavazzi R, Camboni G, Damia G. The tyrosine kinase inhibitor E-3810 combined with paclitaxel inhibits the growth of advanced-stage triple-negative breast cancer xenografts. Mol Cancer Ther. 2013; 12: 131-140.

19. Van der Veldt AA, Lubberink M, Bahce I, Walraven M, de Boer MP, Greuter HN, Hendrikse NH, Eriksson J, Windhorst AD, Postmus PE, Verheul HM, Serne EH, Lammertsma AA, et al. Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell. 2012; 21: 82-91.

20. Ma J, Pulfer S, Li S, Chu J, Reed K, Gallo JM. Pharmacodynamic-mediated reduction of temozolomide tumor concentrations by the angiogenesis inhibitor TNP-470. Cancer Res. 2001; 61: 5491-5498.

21. Ma J, Waxman DJ. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Mol Cancer Ther. 2008; 7: 3670-3684.

22. Claes A, Wesseling P, Jeuken J, Maass C, Heerschap A, Leenders WP. Antiangiogenic compounds interfere with chemotherapy of brain tumors due to vessel normalization. Mol Cancer Ther. 2008; 7: 71-78.

23. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007; 11: 83-95.

24. Ramalingam SS, Dahlberg SE, Belani CP, Saltzman JN, Pennell NA, Nambudiri GS, McCann JC, Winegarden JD, Kassem MA, Mohamed MK, Rothman JM, Lyss AP, Horn L, et al. Pemetrexed, Bevacizumab, or the Combination As Maintenance Therapy for Advanced Nonsquamous Non-Small-Cell Lung Cancer: ECOG-ACRIN 5508. J Clin Oncol. 2019; 37: 2360-2367.

25. Lai X, Friedman A. How to schedule VEGF and PD-1 inhibitors in combination cancer therapy? BMC Syst Biol. 2019; 13: 30.

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

My take of rapamycin is based on this paper. I tried it in 2006, 3 times in the presence of 2 scary witnesses

https://t.co/cuKmqbTjm4

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

Rapamycin in ischemic stroke: Old drug, new tricks?

https://t.co/8wfTBbwlhG

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

So obvious, if you read... below

https://t.co/AxObSemsbx

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

MEK inhibitors for the treatment of non-small cell lung cancer

https://t.co/raSxfP2lqt

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

Does a Real Anti-Aging Pill Already Exist?

https://t.co/PnELGJjI7j
https://t.co/CFuPusPbxX › news › features › does-a-r...
Feb 13, 2015 — Blagosklonny says the drug has fewer side effects than aspirin. Source: Mikhail Blagosklonny. Rapamycin works at a fundamental level of cell ...

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

“Bad luck” hypothesis and cancer prevention

https://t.co/1CRYn1eK8e

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

1/3
My Book "My battle with cancer" became popular in Russian News. I received email with several old (B&W, guess what year? before USSAR collapsed) and a 10 years ago color photos with the same girl, wow , such luck.

[rick burch @rickburch4]

@Marion436842126 @AQFanV @holmanm @Support I’ve been taking serolimus for 4 years now based on this guys work. What are your thoughts on mTOR and reductase, are they both in the cellular reproductive chain?

https://t.co/sFTVndgaeG

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

Aging: ROS or TOR?
In 2008, my article ended with the sentence "My prediction is that five years from now, current opponents will take the TOR-centric model for granted, which then will become new dogma (ironically)"

https://t.co/khVKyHKt7r

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

Cancer prevention with rapamycin

https://t.co/7RqERXpnQX

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

Ten years ago.
2014, Russia

[Mikhail V. Blagosklonny, MD PhD Professor Oncology @Blagosklonny]

My fairy tale about rapamycin, immortality and weight loss.

Introducing a first combo of rapamycin and common drugs

Dr. Alan Green later called it "the Koschei cocktail"

https://t.co/9EAnIXfPHw