Experimental Oncology

In our laboratory, we investigate the interrelationship between tumor growth and the host's immune system to provide knowledge for the design of effective immunotherapies against cancer. The laboratory has many murine tumors of various origins and varying degrees of immunogenicity.

Chair: Raúl Ruggiero, PhD

Independent investigator – CONICET

ruloruggiero@yahoo.com.ar

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New therapeutic strategies against metastases based on the design of molecules derived from meta-tyrosine, the main factor responsible for the phenomenon of concomitant antitumor resistance.

Meta-tyrosine was shown to effectively inhibit and even eliminate established metastases from both murine and human tumors (the latter growing in immunocompromised mice). However, treatment with meta-tyrosine presents three difficulties. The first is that the relatively low metastatic burden achieved its most pronounced effect. When it increased, the effects tended to decrease. The second difficulty is that its ability to dissolve in water or physiological solution is relatively low since it is difficult to reach a concentration greater than 5 mg/ml. The third is that its bioavailability for tissues is not high since, after one hour of intravenous inoculation, its blood concentration drops by half and disappears completely after two hours. Hence the search aimed at chemically designing new molecules derived from meta-tyrosine that, as well as being non-toxic, can be more effective against higher metastatic loads, be more soluble in water or physiological solution, which will allow the use of therapeutic doses older and have good bioavailability.

Relationship between senescence and carcinogenesis.

Liver tumors are induced with a dose of diethylnitrosamine applied to 15-day-old C3H mice. About 500 tumors are usually produced per liver six months after applying the carcinogen, and it is determined whether the appearance of tumors is preceded by the emergence of liver damage and senescence phenomena in the liver. It is evaluated whether the tumors are located preferentially or exclusively in senescent areas or if they are located at random in senescent and non-senescent areas. The mutational profile of the tumors will be studied, and it will be evaluated whether the mutations that typify them are found only in the tumor tissues or in the normal tissue located far from the senescent areas. If “oncogenic” mutations were also found in normal tissue, one wonders why they did not develop in tumors. Experiments of transplantation of tumors and apparently «normal» tissue to senescent and non-senescent areas will allow us to answer this question. Previous experiments in our laboratory that we want to confirm and extend have suggested that an injured organ that has experienced a significant decrease in its reparative capacity (senescence) is the precondition for the appearance of clinically perceptible tumors and that these would behave as repair attempts that, though futile, they would not be autonomous but would constantly be stimulated to grow directed by the regenerative signals of the injured organ. This conception of cancer as having a biological meaning – although not a physiological value – modifies the fundamentals of carcinogenesis and encourages the thinking of therapies that are very different from those currently used, based mainly on restoring the standard conditions of the organ and not so much, or not only, restricted to eliminating tumor cells.

Antitumor immunotherapy and the immunostimulatory theory of cancer.

Although immune-checkpoint inhibitors (ICI) are a promising therapy against cancer, the treatment sometimes produces a deleterious side effect known as tumor hyper-progression (HPD, abbreviation of English hyper-progressive cancer disease) characterized by acceleration of neoplastic growth and reduced survival. In order to understand the elusive mechanisms of HPD, we have tested ICI therapy on murine tumors that differed in their immunogenicity and their ability to generate metastases. It was shown that ICI was therapeutically effective against both tumors (in direct proportion to their immunogenicity), but only when the tumors to be treated were incipient. In contrast, when tumors were larger or tumors recurred after incomplete removal, ICI treatment accelerated tumor growth. This acceleration occurred paradoxically associated with a slight increase in the antitumor immune response induced by ICIs, suggesting that, as predicted by the immunostimulatory theory of cancer, a weak immune response – unlike a strong one – does not produce a null effect but rather an exacerbation of tumor growth. In a first attempt to counteract the phenomenon of HPD, we combined ICI with meta-tyrosine (which counteracts immunosuppressive signals by mechanisms different from ICI) and with a selective inhibitor of the p38 signaling pathway (because we had previously shown that the acceleration of the tumor growth due to a weak immune response was associated with the p38 pathway). Combination treatment strongly retarded the growth of large tumors and cured 80% of mice with local recurrences and 60% of mice with established metastases after tumor removal. These results encourage further studies to achieve better therapeutic results.

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