Recent developments in pre-clinical screening tools, that more reliably predict the clinical effects and adverse events of candidate therapeutic agents, has ushered in a new era of drug development and screening. However, given the rapid pace with which these models have emerged, the individual merits of these translational research tools warrant careful evaluation in order to furnish clinical researchers with appropriate information to conduct pre-clinical screening in an accelerated and rational manner. This review assesses the predictive utility of both well-established and emerging pre-clinical methods in terms of their suitability as a screening platform for treatment response, ability to represent pharmacodynamic and pharmacokinetic drug properties, and lastly debates the translational limitations and benefits of these models. To this end, we will describe the current literature on cell culture, organoids, in vivo mouse models, and in silico computational approaches. Particular focus will be devoted to discussing gaps and unmet needs in the literature as well as current advancements and innovations achieved in the field, such as co-clinical trials and future avenues for refinement.
Background/Aim: The purpose of this study was to assess patients' use of a crowdfunding platform to raise funds for radiation treatment and to better understand the direct and indirect costs associated with treatments. Materials and Methods: The GoFundMe crowdfunding database was queried for four unique categories related to radiation treatment campaigns. Covariates identified included clinical and demographic variables, and associations between amount raised and these predictors were analyzed using a generalized linear model. Results: While 56% percent of campaigns cited direct costs associated with treatment, 73.4% of campaigns cited indirect costs related to treatment. Indirect expenses related to travel (31.7%) as well as living expenses (29.2%) were cited most often across all four treatment categories. Conclusion: This study enhances understanding regarding patients use of crowdfunding for radiation treatment. Increased focus should be placed on discussing the indirect costs of care with patients and their families.The United States has observed a promising trend in increased cancer survival with improved screening protocols, advanced medical technologies, and the development of targeted radiation and other treatments (1, 2). These advancements increased cancer survivorship on the world stage (3). However, the "financial toxicity", or exorbitant cost of cancer care in the United States, has increased at a substantial rate. (1) A study characterized the financial toxicity of cancer care for over 9.5 million newly diagnosed Americans over the age of 50 and found 42% of patients reported fully depleting their assets by the second year of their diagnosis (4). Patients, already dealing with the emotional and physical toll of a cancer diagnosis, may resort to radical lifestyle changes that include decreased food spending, selling their possessions and property, borrowing money from others, and declaring bankruptcy due to treatment expenses and the associated costs of treatment (5).When compared with the cost of chemotherapy and pharmaceutical therapy in cancer care, radiation treatment is a relatively cost-effective modality that accounts for less than ten percent of the total costs of cancer care (6, 7). Yet, approximately half of all patients with cancer will receive radiation therapy as part of their treatment course (6), and the cost of radiation therapy in the United States may contribute to financial toxicity for patients and families (8). Furthermore, distinct forms of radiation therapy may have substantially different costs associated with treatment. Considering the financial toxicity of cancer therapy and the personal life changes that may occur as a result, patients and families have begun to use crowdfunding sources as an avenue to fund treatments and the expenses associated with cancer care. Despite its popular use, much is not known regarding patient and family use of crowdfunding platforms in order to fund cancer treatment. Few studies to date have performed an indepth analysis of crowdfunding platf...
Immunotherapy is a rapidly evolving treatment paradigm that holds promise to provide long-lasting survival benefits for patients with cancer. This promise, however, remains unfulfilled for the majority of patients with gastrointestinal (GI) cancers, as significant limitations in efficacy exist with immune checkpoint inhibitors (ICIs) in this disease group. A plethora of novel combination treatment strategies are currently being investigated in various clinical trials to make them more efficacious as our understanding of molecular mechanisms mediating resistance to immunotherapy advances. In this article, we summarize the current status of immune checkpoint blockade in GI cancers and discuss the biological rationales that underlie the emerging treatment strategies being tested in ongoing clinical trials in combination with ICIs. We also highlight the promising early results from these strategies and provide future perspectives on enhancing response to immunotherapy for patients with GI cancers.
Immunotherapy (IMT) has produced complete responses in a subset of colorectal cancer (CRC) patients harboring tumors molecularly characterized as microsatellite instable (MSI). However, the majority (95%) of CRC patients with microsatellite stable (MSS) tumors remain virtually unresponsive. There is strong rationale that with the correct approach, IMT can elicit potent anti-tumor responses in CRC-MSS patients. Prior studies have demonstrated that histone deacetylase inhibitors (HDACi) have the potential to enhance tumor immunogenicity as indicated by the decreased effectiveness of monotherapy in the absence of an adaptive immune system and augmentation of responses to IMT. Whether HDACi treatment enhances anti-tumor immune responses by increasing tumor immunogenicity, directly affecting T-cells, or both, remains unknown. Therefore, we explored the differential effects of HDAC inhibitors with distinct specificities have directly on tumor and T-cells which will be critical in designing optimal therapeutic strategies. Results: First, we compared the direct cytotoxic effects on murine CRC cells and found that pan-HDACi caused cell death, while class I/II and HDAC VI inhibitors did not affect survival even at high concentrations (1μM). Evaluation of changes to immunogenic proteins revealed modest, but similar increases in immunogenic proteins (MHC-I, ICOSL, PD1L, CD80) across HDACi compounds. Strikingly, the co-stimulatory ligand CD86 was increased only with an HDAC VI inhibitor. Next, we sought to determine whether distinct inhibitors also had direct effects on T-cells during stimulation. Interestingly, we found all inhibitors did not affect TNFα production but caused a drastic decrease in IL-2, an important cytokine for T-cell survival and function. Moreover, this effect was found at low concentrations of HDACi and thus appear more sensitive. Conclusions: These results demonstrate for the first time that different classes of HDAC inhibitors have unique properties in affecting tumor growth and immunogenicity. Conversely, all classes blocked IL-2 production by T-cells but not TNFα, suggesting a common mechanism in affecting select components of T-cell effector responses. Although previous studies showed synergy with IMT, our data suggests that HDACi detrimentally affect T-cells directly. Based on this, an optimal strategy for combination with IMT may entail priming the tumor microenvironment and stopping HDACi during T-cell targeted IMT. Future studies are underway to determine whether HDACi effects on T-cells are reversible, the kinetics of these effects and their impact on T-cell co-receptor expression. Collectively, these studies will help identify the most promising HDACi, immunotherapeutic targets and the sequence of combination therapy. Citation Format: Nisha Holay, Uma Giri, Mihailo Miljanic, Milad Soleimani, Omar Shaikh, Anna Capasso, Carla L. Van Den Berg, Gail Eckhardt, Todd Triplett. Unleashing the potential of HDACi to augment immunotherapy for the treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1088.
In this commentary, we describe the potential of highly ablative doses utilizing Stereotactic Body Radiation Therapy (SBRT) in single or few fractions to enhance immune-responsiveness, how timing of this approach in combination with immune-checkpoint inhibitors may augment treatment-effect, and whether Personalized Ultrafractionated Stereotactic Adaptive Radiation Therapy (PULSAR) is an avenue for future advancement in the continued endeavor to foster a systemic effect of therapy beyond the radiation treatment field. The ablative potential of SBRT may support an increase in tumor-antigen presentation, enhancement of immune-stimulatory components, and an improvement in tumor-microenvironment immune cell infiltration. Furthermore, the latest advancement of ablative radiation delivery is PULSAR-based therapy, whereby ablative doses are delivered in pulses of treatment that may be several weeks apart, combined with adaptive treatment to tumor changes across time. The benefits of this novel approach include the ability to optimize direct tumor control by assessment of tumor size and location via dedicated imaging acquired prior to each delivered pulse, and further potentiation of immune recognition through combination with concurrent immune-checkpoint blockade.
Background: Studies have shown that MEK inhibitors (MEKi) can reduce tumorigenic growth signaling in colorectal cancer (CRC) through inhibition of the RAS pathway which is upregulated in over 40% of CRC tumors, while HDAC inhibitors (HDACi) lead to cell cycle arrest, inhibit angiogenesis, and induce apoptosis in neoplastic cells. In addition to a direct effect on neoplastic cells, MEKi have also demonstrated the potential to increase immune response to the tumor through upregulation of MHC I on tumor cells, induction of intra-tumoral T-cell infiltration, and enhancement of anti-PDL1 activity. HDAC inhibitors lead to epigenetic alterations which have similarly shown an ability to increase tumor immunogenicity, leading to the hypothesis that these agents may be combined with immunotherapy treatments for enhanced anti-tumor effect. In this study we first analyzed the effect of MEKi and HDACi combination treatment in both resistant and sensitive CRC cell lines to assess for synergy in the attenuation of cancer cell proliferation. We then demonstrated the effect of combination MEKi and HDACi therapy on tumor immunogenicity through increased expression of tumor immune markers. Methods: We assessed the efficacy of a novel MEKi agent, HL-085, in comparison with trametinib in six different CRC cell lines. Treatment with each agent was separately administered with a maximum concentration of 10 uM. Similarly, five different HDAC inhibitors were tested in each of these cell lines, with a maximum concentration of 1 uM. Optimal combination of MEK inhibitor HL085 and HDAC inhibitor class I/II (OKI-005) were then chosen based on this data. Cellular proliferation was assessed after 72 hours with Cell Titer Glo. Flow cytometry of a panel of immunogenic markers was then performed alongside a viability stain to assess for expression level changes of MCH class I in CRC cells. Results: Combinatorial effects of dual treatment with MEK inhibitor HL085 and HDAC inhibitor OKI-005 are observed in both resistant and sensitive cell lines with synergistic effect produced in the SW620 and Lovo cell lines (MEKi sensitive) as well as the GP2D (MEKi resistant) cell line. No synergistic effect was observed in the HCT15, DLD1 and LS513 cell lines. Flow cytometry showed an increase in MHC class I expression in neoplastic cells with combined MEKi and HDACi treatment compared to individual agent treatment and control, demonstrating increased immunogenicity of CRC cells with combination treatment. Conclusions: Combination treatment with a novel MEK inhibitor HL085 and the HDAC inhibitor OKI-005 demonstrates synergy in three out of six colorectal cancer cell lines. We further show increased immunogenicity of CRC cells through enhanced expression of MCH I on tumor cell surface, indicating rationale for further investigation of combination MEKi and HDACi with immunotherapy in the treatment of metastatic colorectal cancer. Citation Format: Mihailo Miljanic, Nisha Holay, Anna Capasso, Todd Triplett, Milad Soleimani, Uma Giri, Carla Van Den Berg, Gail Eckhardt. Attenuating colorectal cancer cell growth and enhancing immunogenicity through rational combination of MEK and HDAC inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4753.
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