Social Media

Here you’ll find some of our social media activities, including blogging and a YouTube channel. The blog posts immediately below are what we refer to as 'micro-reviews'.

Finding Gold in an Abandoned Mine: Drug Combos & Repurposing

With the accumulation of a large repertoire of medicinal agents, the availability of massive chemical libraries, and the coming of age of high-throughput and rational methods, much interest has developed towards the discovery of therapies based on novel drug combinations [1,2]. The concept relies on additive, and preferably synergistic, efficacy afforded by the activity of two or more agents in parallel. The approach holds promise for circumventing resistance issues by hitting multiple targets/pathways in unison and potentially mitigating toxicity problems by virtue of lowering dosage requirements. A major aspect of drug combo discovery efforts entails drug repurposing/repositioning, in which approved, investigational, and notably abandoned (‘shelved’) agents are found to have therapeutic applications outside of their original indications. A big advantage of such drug-reinvention is that a substantial part of the development process may already be in-hand, in particular knowledge of toxicity/safety profiles and other pharmacological attributes as well as possible manufacturing and supply solutions (for the monotherapies; translating to savings in time & money). Indeed, repurposing is a driving force behind current efforts to find treatments for rare (orphan) diseases.

A study just came out that entailed screening >5000 targeted agent combinations across 81 non-small cell lung cancer cell lines [3]. Several notable generalizations could be drawn that include a profound heterogeneity of response to a given drug or combination across the cell lines, consistent with clinical observations of response heterogeneity even within molecularly stratified patients. A key finding is that synergistic drug combinations, or simply combinations resulting in a strong gain in efficacy, are rarely encountered by chance due to a high context-dependency. This is in line with previous investigations encompassing also an analogous study of last year that entailed screening 2,025 clinically relevant two-drug combinations across 125 breast, colorectal, and pancreatic cancer cell lines [4]. In fact, combinations of targeted agents are most likely to be efficacious or synergistic, which tends to result from hitting a single or multiple interacting pathways as opposed to targeting functionally distinct/noninteracting cellular modules, providing a basis for guided (rational) initiatives to develop combinatorial therapies. These tumor cell-based screening approaches are validated through recapitulating established synthetic lethal and other synergistic drug combinations and therefore provide a platform for lead generation that may help catalyze cancer therapy discovery, including the recycling of abandoned drugs.

[1] Jin H, Wang L, Bernards R. (2023) Rational combinations of targeted cancer therapies: background, advances and challenges. Nat. Rev. Drug Discov. 22(3): 213–234.
[2] Pushpakom S, et al. (2019) Drug repurposing: progress, challenges and recommendations. Nat. Rev. Drug Discov. 18(1): 41–58.
[3] Nair NU, et al. (2023) A landscape of response to drug combinations in non-small cell lung cancer. Nat. Commun. 14(1): 3830.
[4] Jaaks P, et al. (2022) Effective drug combinations in breast, colon and pancreatic cancer cells. Nature. 603(7899): 166–173.

Many Might Have Thought Platinum Drugs Were Handed Their Hat, but Cancer Patients Don’t.

It has been 45 years since cisplatin was FDA-approved for treating cancer [1]. This first of the platinum-based drugs is nearly 100% curative for early-diagnosed testicular cancer. Carboplatin and oxaliplatin are alternative platinum drugs approved worldwide that were developed subsequently based on the cisplatin framework. Five additional platinum compounds have been approved for clinical use in specific countries. In fact, an estimated 46% of patients undergoing chemotherapy are still administered a platinum drug [2], which might come as a surprise to some given the ongoing developments in highly sophisticated cancer treatments that include targeted strategies and immunotherapies. Interestingly, high-impact reviews are periodically published that claim a resurgence of interest in platinum-based treatments, and this can be largely attributed to an ever-increasing understanding of drug action and resistance mechanisms [3,4]. The expectation is that platinum drugs will remain part of the standard care, for at least certain cancers, for some time to come and that optimized combinations with immunotherapies will comprise an important class of regimen [4,5]. For instance, Bristol Myers Squibb, who licensed cisplatin and carboplatin, has made recent announcements on approvals for platinum drug combinations with the PD-1 immune checkpoint inhibitor, Opdivo (nivolumab; monoclonal antibody) [6,7].

[1] Gandin V, Hoeschele JD, Margiotta N. (2023) Special Issue "Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0". Int. J. Mol. Sci. 24(9): 7917.
[2] Alassadi S, Pisani MJ, Wheate NJ. (2022) A chemical perspective on the clinical use of platinum-based anticancer drugs. Dalton Trans. 51(29): 10835–10846.
[3] Kelland L. (2007) The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer. 7(8): 573–84.
[4] Rottenberg S, Disler C, Perego P. (2021) The rediscovery of platinum-based cancer therapy. Nat. Rev. Cancer. 21(1): 37–50.
[5] Tsvetkova D, Ivanova S. (2022) Application of Approved Cisplatin Derivatives in Combination Therapy against Different Cancer Diseases. Molecules. 27(8): 2466.
[6] Bristol Myers Squibb press release
[7] Bristol Myers Squibb press release

The artificial sweetener, sucralose, may be toxic more specifically because of sucralose-6-acetate, a metabolite and an impurity that remains from its manufacture [1].

[1] Schiffman SS, Scholl EH, Furey TS, Nagle HT. (2023) Toxicological and pharmacokinetic properties of sucralose-6-acetate and its parent sucralose: in vitro screening assays. J. Toxicol. Environ. Health B Crit. Rev. 1–35.

Can Life Quality vs Quantity be Quantified?

Haven’t we all thought about, and perhaps dwelled upon at times, what would make me happy/happier, how long might I live, and even the combination of the two? Live long and prosper, right?! The pursuit of happiness, eh?! Well, although the topic is controversial and seemingly complex [1,2], a large body of work accumulating over many decades of research suggests that a state of positivity— being happy, content/joyous, optimistic— also keeps us alive longer [3–9]. In fact, the mechanistic underpinnings of how positive emotions modulate our neurophysiology are also coming to light [10]. If the link is robust and causative, there is a double whammy here, in that the ‘quality’ of your life, as reflected by your emotional status, also promotes your quantity of life. This provides an extra incentive to strive for contentment and optimism within one’s life circumstances whenever possible.

If there is indeed a causative relationship between emotional positivity and longevity, then an individual could be ascribed an ‘intrinsic longevity’— theoretical lifespan coinciding with a neutral emotional status— and an ‘adjusted longevity’ (actual lifespan), which takes into account the impact of one’s emotional disposition. The question is then what is the magnitude of impact that emotional disposition can have on one’s ultimate lifespan?

Already before 2010, there were a number of studies that had demonstrated a significant correlation between happiness (subjective well-being) and longevity, with implied causality [5]. One study concluded: “It appears that happiness does not predict longevity in sick populations, but that it does predict longevity among healthy populations. So, happiness does not cure illness, but it does protect against becoming ill. The effect of happiness on longevity in healthy populations is remarkably strong. The size of the effect is comparable to that of smoking or not [4].” This work reported that happy people live 7.5 to 10 years longer, which is consistent with a meta-analysis of 24 other studies estimating an increase in longevity of 14% [3], further supported by a more recent investigation [6].

Looking from the standpoint of an analogous qualifier of emotional disposition, optimism, other investigations have reached the same overall conclusion as judged by the measure of happiness per se. One study found a 15% longer lifespan in the highest-relative-to-lowest optimism quartiles [7], whereas another report evaluating a racially diverse cohort found only a 5.4% longevity difference in the same respect [8]. Although in one large-cohort investigation, researchers argued that happiness and related measures of well-being do not directly affect mortality [1], their work has been cited for critical flaws in study design and data analysis [11]. Nonetheless, other works have also suggested that the relationship between happiness and longevity is decisively non-linear, such that unhappy people have shorter lives, but otherwise the remaining distribution of happiness does not influence longevity [2].

In terms of an overall consensus, it seems safe to conclude that a positive emotional state increases lifespan. However, so many more questions remain given the complex network of factors at play, whereby notably social integration (as opposed to isolation) and positive relationships are strongly connected with happiness/optimism and physiological well-being [12]. In the end, so to speak, I think it is interesting to speculate that we may one day be able to quantify the impact of our states of mind and emotions on our physiology and moreover how this may affect not only our life quality but also our life quantity.

[1] Liu B., Floud S., Pirie K., Green J., Peto R., & Beral V.; Million Women Study Collaborators. (2016) Does happiness itself directly affect mortality? The prospective UK Million Women Study. Lancet. 387(10021): 874–881.
[2] Headey, B., & Yong, J. (2019) Happiness and longevity: Unhappy people die young, otherwise happiness probably makes no difference. Soc. Indic. Res. 142(2): 713–732.
[3] Howell, R.T., Kern, M.L, & Lyubomirsky, S. (2007) Health benefits: Meta-analytically determining the impact of well-being on objective health outcomes. Health Psychol. Rev. 1(1): 83–136.
[4] Veenhoven, R. (2008) Healthy happiness: effects of happiness on physical health and the consequences for preventive health care. J. Happiness Stud. 9(3): 449–469.
[5] Frey, B.S. (2011) Psychology. Happy people live longer. Science. 331(6017): 542–543.
[6] Lawrence, E.M., Rogers, R.G., Wadsworth, T. (2015) Happiness and longevity in the United States. Soc. Sci. Med. 145: 115–119.
[7] Lee, L.O., James, P., Zevon, E.S., Kim, E.S., Trudel-Fitzgerald, C., Spiro, A. 3rd, Grodstein, F., & Kubzansky, L.D. (2019) Optimism is associated with exceptional longevity in 2 epidemiologic cohorts of men and women. Proc. Natl. Acad. Sci. USA. 116(37): 18357–18362.
[8] Koga, H.K., et al. (2022) Optimism, lifestyle, and longevity in a racially diverse cohort of women. J. Am. Geriatr. Soc. 70(10): 2793–2804.
[9] The Harvard Study of Adult Development (Second site).
[10] Alexander, R., et al. (2021) The neuroscience of positive emotions and affect: Implications for cultivating happiness and wellbeing. Neurosci. Biobehav. Rev. 121: 220–249.
[11] Diener E, Pressman SD, Lyubomirsky S. (2015) Can 1 million women be wrong about happiness and health? Los Angeles Times. A21.
[12] Yang YC, Boen C, Gerken K, Li T, Schorpp K, Harris KM. (2016) Social relationships and physiological determinants of longevity across the human life span. Proc. Natl. Acad. Sci. USA. 113(3): 578–583.