A combined treatment for an aggressive lymphoma subtype.

Lymphomas are a group of diseases of the lymphoid tissue, a tissue mainly composed of cells named lymphocytes, which are responsible of immune response. Lymphomas are accompanied by lymph nodes swelling, due to the accumulation of healthy and cancer lymphocytes.

Lymphomas are very heterogeneous group of diseases from a molecular and clinical point of view; they can be roughly classified according to the cell subtype affected (eg B cells, T cell, NKT), the morphology of the cells and so on.

MYC and BCL2 proteins in lymphomas. Double Hit Lymphoma (DHL) is a subtype associated with a poor outcome with current treatments, and is characterized by anomalous expression -overexpression- of the proteins MYC and BCL2 in malignant B cells. Therefore, new, more efficient treatments are required. MYC has a double role in cell physiology, controlling both proliferation and apoptosis (cell process resulting into cell death). In DHL, the pro-apoptotic activity of MYC is inhibited by the concurrent overexpression of BCL2 protein. Without the “apoptotic brake” normally exerted by BCL2, and the untouched MYC-controlled proliferative activity, malignant B cells proliferation is uncontrolled, causing lymphomas.

Inhibiting BCL2. Since BCL2 normally represses MYC pro-apoptotic activity, inhibiting BCL2 (removing the repression on the pro-apoptotic activity of MYC) results into a re-gain of MYC-modulated pro-apoptotic activity. Previous studies revealed, indeed, the effect of BCL2 inhibitor Venetoclax in limiting cancer cells proliferation, with promising results. In line with these results, reinforcing the effect of Venetoclax contributes to the eradication of DHL cells.

An antibiotic against Myc-elicited lymphomas. Tigecycline is an antibiotic having anti-cancer effect –as shown in several tumor types- likely due to the inhibition of mitochondrial translation, by acting on mitochondrial ribosomes. Genes coding for proteins involved in mitochondrial translation (such as mitochondrial ribosomes, involved in the translation of mitochondrial DNA*) are activated and have a key role in lymphoma initiation and maintenance. The treatment of lymphoma cells (where tumorigenesis is elicited by MYC iperactivation) with the antibiotic Tigecycline results into reduced cancer cells survival in in vitro assays, and extended lifespan of lymphoma bearing mice.

Why is that? Tigecycline inhibits the protein required for tumor progression, such as those of the mitochondrial translation machinery.

Therefore, the combined action of the BCL2 inhibitor Venetoclax and Tigecycline (inhibiting components of the mitochondrial translation known to control lymphoma maintenance) causes tumor eradication in in vivo models.

Tigecycline is an example of a successful Drug Repurposing, a quite common practice in today’s clinical studies, where a drug normally used in a certain therapeutic area is tested for the treatment of different diseases. This is normally encouraged, as it bypasses all the steps required to certify the safety of a drug and admit it on the market, which are long and costly, taking advantage, instead, of drugs that are already approved, meaning drugs that already went through the numerous toxicity tests set by the law.

I personally always considered Drug Repurposing a slightly unusual approach, reasoning that if a drug has been tested and considered efficient for the treatment of a disease, it means that it should be specific for it and, in my opinion, specificity should not go hand-in-hand with broader effects on different pathologies. I always thought that interfering with precise mechanisms at the basis of a disease should not affect other cell processes, in order to limit side effects.

However, when carefully supported by research data highlighting and strengthening the rationale of their usage in the underlying common molecular/biological mechanism, results definitely support drug repurposing’s success.

*Mitochondria are small organelles present in cells. Their primary function is production of ATP,  a key molecule in cell metabolism. Mitochondria have their own DNA, which is replicated, transcribed and successively translated into protein through the mitochondrial specific translation system (together with proteins translated from the nuclear DNA and imported inside the mitochondria), which comprises its own structures: the ribosomes. 

Reference: Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC/BCL2 double-hit B cell lymphoma. Ravà M, D'Andrea A, Nicoli P, Gritti I, Donati G, Doni M, Giorgio M, Olivero D, Amati B. Sci Transl Med. 2018