<p dir="ltr">Over the last century, cancer immunotherapy has become an attractive field due to the popularity of checkpoint blockades and adoptive cell therapy. Though these new frontier therapeutics are effective for certain populations, they’ve had either adverse effects on others or are non-efficacious when used to treat “cold tumors”. Hence, newer strategies are needed to sensitize cold tumors into immune-responsive “hot tumors”, which synergize with checkpoint blockades. The cyclic GMP-AMP synthase-Stimulator of INterferon Genes (cGAS-STING) pathway has been identified as a pathway that can initiate T cell infiltration and turn cold tumors into hot tumors. Therefore, STING agonists have been identified as potential remedies that could help bend the curve to increase the survival rate of cancer patients if combined with anti-PD1 and anti-CTLA4 therapies.</p><p dir="ltr">2’3’-cGAMP is a master regulator of the innate immune system and is produced by cGAS upon cancer deregulation as well as bacterial and viral infection. Although 2’3’-cGAMP is a nanomolar affinity binder to STING and has vast immunostimulatory potential, it is plagued by several limitations that prevent its use in vivo. Most medicinal chemists have focused on making phosphorothioate derivatives which circumvents 2’3’-cGAMP’s limitations, but synthesizing these analogs presents a synthetic challenge. Also, these derivatives are commonly administered via intratumoral injection, which is not an attractive mode of delivery. This dissertation tries to address some of these challenges and provide a newer platform to develop CDN-based STING agonists.</p><p dir="ltr">We describe a novel class of phosphorothioester-linked cyclic dinucleotides (endo-S-CDNs) as excellent STING agonists. Showing through structural-activity relationship (SAR) which groups are tolerated or detrimental for STING binding and cellular activity. Also, determining that these 5’-phosphorothioester-linked CDNs are resistant to cleavage by clinically relevant phosphodiesterases (PDEs). Finally, we discuss how this novel class of CDNs is suitable for subcutaneous dosing to clear tumors in different mouse models.</p>

A expressão de Smads e de membros da família AP1/ jun-fos podem refletir alterações da via de TGFb, uma via importante para o câncer epidermóide de cabeça e pescoço (HNSCC). Encontramos expressão aumentada dos mRNAs das Smads1-8 em HNSCC em comparação com tecido normal adjacente, por RPA. Além disso, as curvas de sobrevida de Kaplan Meier e a análise multivariada mostraram que a Smad6+ parece ser um fator determinante de bom prognóstico em HNSCC. Quanto a família AP-1, mensurado por Northern blot, somente Fra-1 mostrou-se aumentado no tumor e associado à presença de linfonodos comprometidos. Nossos dados sugerem que a positividade de Smad6 possa ser marcador de bom prognóstico em HNSCC / Smad and AP1 messenger RNA expression may underlie disruptions affecting TGFb signaling in head and neck squamous cell carcinoma (HNSCC). Analysis of Smads1-8 mRNA expression by RPA has shown Smad expression is globally increased in tumor as compared to adjacent normal tissue. Kaplan Meier survival curves and multivariate analysis revealed that Smad6 positivity in tumor was an independent good prognostic factor in HNSCC. In relation to AP-1, as measured by Northern blot, only Fra-1 was overexpressed in tumor and directly related to the presence of lymph node involvement. Our data suggest that Smad6 may be a marker of good prognosis in HNSCC

A expressão de Smads e de membros da família AP1/ jun-fos podem refletir alterações da via de TGFb, uma via importante para o câncer epidermóide de cabeça e pescoço (HNSCC). Encontramos expressão aumentada dos mRNAs das Smads1-8 em HNSCC em comparação com tecido normal adjacente, por RPA. Além disso, as curvas de sobrevida de Kaplan Meier e a análise multivariada mostraram que a Smad6+ parece ser um fator determinante de bom prognóstico em HNSCC. Quanto a família AP-1, mensurado por Northern blot, somente Fra-1 mostrou-se aumentado no tumor e associado à presença de linfonodos comprometidos. Nossos dados sugerem que a positividade de Smad6 possa ser marcador de bom prognóstico em HNSCC / Smad and AP1 messenger RNA expression may underlie disruptions affecting TGFb signaling in head and neck squamous cell carcinoma (HNSCC). Analysis of Smads1-8 mRNA expression by RPA has shown Smad expression is globally increased in tumor as compared to adjacent normal tissue. Kaplan Meier survival curves and multivariate analysis revealed that Smad6 positivity in tumor was an independent good prognostic factor in HNSCC. In relation to AP-1, as measured by Northern blot, only Fra-1 was overexpressed in tumor and directly related to the presence of lymph node involvement. Our data suggest that Smad6 may be a marker of good prognosis in HNSCC