Preclinical Study Finds Cancer Stem Cell Inhibitor Sensitizes Colon Cancer Cells To Immunotherapy

MedicalResearch.com Interview with:
Dr. Yuan Gao

Assistant Investigator at Boston Biomedical

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Colorectal cancer (CRC) is the third most commonly diagnosed malignant disease and third most frequent cause of cancer-related death in the United States. Standard treatment for unresectable metastatic CRC currently includes first and second line 5-fluorouracil (5-FU)-based chemotherapy regimens. However, CRC patients often develop chemoresistance. Recently, immunotherapy has emerged as a revolutionary new treatment for CRC. However, with the exception of a small percentage of CRC patients that display microsatellite instability (MSI), the vast majority of colorectal cancer patients have been found to be resistant to immune checkpoint therapies.

Cancer stem cells (CSCs), a highly malignant tumor cell subpopulation capable of self-renewal, are considered to be fundamentally responsible for malignant growth and tumor recurrence. Emerging evidence indicates that CSCs and cancer stemness pathways, such as STAT3, beta-Catenin, CD44 and Nanog, are involved in the immune evasion of cancers. BBI-608 (napabucasin) is an orally-administered first-in-class cancer stemness inhibitor that works by targeting STAT3. In this study, we investigated the effect of cancer stemness inhibition on sensitizing colorectal cancer to immune checkpoint inhibitors in preclinical models.

In the syngeneic microsatellite stable (MSS) tumor model, CT26, an anti-PD-1 antibody delivered as a monotherapy, produced low level and temporary antitumor activity with rapid development of complete resistance to anti-PD-1 treatment. The anti-PD-1 antibody-treated CT26 tumors exhibited increased p-STAT3 activation and overexpression of a variety of stemness factors, as well as enrichment of sphere-forming stemness-high cancer cells. Napabucasin was able to reduce basal as well as anti-PD1-induced STAT3 activation and other CSC features within CT26 tumors. The combination of a stemness inhibitor – napabucasin – with the anti-PD-1 antibody led to tumor complete response (CR) in all treated CT26 tumors, with 40 percent of the mice remaining tumor-free for 30 days following treatment termination. This combination also had a synergistic effect on the influx of tumor infiltrating CD8+ T cells, which likely contributed to the rapid tumor regression. Finally, mice CR-induced by napabucasin and the anti-PD-1 antibody were able to reject CT26 tumors upon re-challenge, but not the unrelated breast cancer 4T1 tumors.

MedicalResearch.com: What should readers take away from your report?

Response: Our data suggest cancer stemness pathways contribute to immunotherapy resistance in MSS CRC, a subtype representing the vast majority of colorectal cancer cases. Furthermore, inhibition of cancer stemness by BBI-608 sensitizes colorectal cancer to immune checkpoint inhibition, producing striking regression in a large proportion of the tumors treated.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: This study provides compelling preclinical evidence to support the investigation of the combination of napabucasin with immune checkpoint inhibitors in CRC. While this study specifically investigated the combination with anti-PD-1, the combination with other immunotherapies could be studied as well.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation: AACR 2017 Abstract

Inhibition of cancer stemness sensitizes colorectal cancer to immune checkpoint inhibitors
Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Gene-silencing RNAs Targeting CTNNB1 and PD-L1 May Attack a Variety of Cancers

MedicalResearch.com Interview with:
Dr. Youzhi Li

Vice President at Boston Biomedical 

MedicalResearch.com: What are the main findings?

Response: RNAi (RNA interference) technology has the potential to target any genes causing disease, including conventionally “undruggable” targets in cancer. One particularly interesting RNAi target in oncology is the CTNNBI oncogene, which encodes the β-Catenin protein whose nuclear form acts as a transcription factor promoting tumorigenesis. Aberrant β-Catenin signaling has been demonstrated in 90 percent of colorectal carcinomas, 40 percent of hepatocellular carcinoma, and 90 percent of non-ductal pancreatic carcinomas. Recent research also suggests active β-Catenin contributes to tumor immune evasion and to the recurrence of melanoma in patients post the check-point blockage immunotherapy.

However, the direct blockade of β-Catenin activity has proved difficult with conventional approaches. While the application of traditional RNAi technology has the potential to block this pathway, in clinical cancer therapy, this approach has proven challenging due to the difficulty in systemic delivery of RNAi to tumor sites located in various organs.

We have recently developed BBI-801, a lipid-based nanoparticle that encapsulates therapeutic aiRNAs targeting CTNNB1 and PD-L1 to simultaneously target immune evasion via both these pathways. Here, we investigate the in vivo delivery and anti-tumor activity of BBI-801.

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Granzyme B Probe Plus PET Scanning Helps Determine Response To Immunotherapy

MedicalResearch.com Interview with:

Ben Larimer, PhD research fellow in lab of Umar Mahmood, MD, PhD Massachusetts General Hospital Professor, Radiology, Harvard Medical School

Dr. Ben Larimer

Ben Larimer, PhD research fellow in lab of
Umar Mahmood, MD, PhD

Massachusetts General Hospital
Professor, Radiology, Harvard Medical School

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:
Although immunotherapies such as checkpoint inhibitors have revolutionized cancer treatment, unfortunately they only work in a minority of patients. This means that most people who are put on a checkpoint inhibitor will not benefit but still have the increased risk of side effects. They also lose time they could have spent on other therapies. The ability to differentiate early in the course of treatment patients who are likely to benefit from immunotherapy from those who will not greatly improves individual patient care and helps accelerate the development of new therapies.

The main purpose of our study was to find a way to separate immunotherapy responders from non-responders at the earliest time point possible, and develop an imaging probe that would allow us to distinguish this non-invasively.

Granzyme B is a protein that immune cells use to actually kill their target. They keep it locked up in special compartments until they get the right signal to kill, after which they release it along with another protein called perforin that allows it to go inside of tumor cells and kill them. We designed a probe that only binds to granzyme B after it is released from immune cells, so that we could directly measure immune cell killing. We then attached it to a radioactive atom that quickly decays, so we could use PET scanning to noninvasively image the entire body to see where immune cells were actively releasing tumor-killing granzyme B.

We took genetically identical mice and gave them identical cancer and then treated every mouse with checkpoint inhibitors, which we knew would result in roughly half of the mice responding, but we wouldn’t know which ones until their tumors began to shrink. A little over a week after giving therapy to the mice, and before any of the tumors started to shrink, we injected our imaging probe and performed PET scans. When we looked at the mice by PET imaging, they fell into two groups. One group had high PET uptake, meaning high levels of granzyme B in the tumors, the other group had low levels of PET signal in the tumors. When we then followed out the two groups, all of the mice with high granzyme B PET uptake ended up responding to the therapy and their tumors subsequently disappeared, whereas those with low uptake had their tumors continue to grow.

We were very excited about this and so we expanded our collaboration with co-authors Keith Flaherty and Genevieve Boland to get patient samples from patients who were on checkpoint inhibitor therapy to see if the same pattern held true in humans. When we looked at the human melanoma tumor samples we saw the same pattern, high secreted granzyme levels in responders and much lower levels in non-responders.

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Trunk and Branch Drivers Distinguish Early vs Late Mutations in Hepatocellular Carcinoma

MedicalResearch.com Interview with:
Sara Torrecilla Recio

PhD Student
Mount Sinai Liver Cancer Program – Division of Liver Diseases Icahn School of Medicine at Mount Sinai
New York, NY

MedicalResearch.com: What is the background for this study?

Response: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which represents the second-leading cause of cancer related death worldwide. The landscape of molecular alterations in HCC has been thoroughly explored using next-generation sequencing technologies in single biopsies of tumors. However, in the recent years it has been demonstrated that not all the regions of a tumor harbor the same molecular alterations. This intra-tumor heterogeneity may lead to a misinterpretation of the molecular landscape of the malignancy since not all the molecular alterations would be captured by single-biopsies.

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Model of RAF Inhibitor Action Provides Roadmap For Resistant Colon and Thyroid Cancer Treatment

MedicalResearch.com Interview with:

Poulikos I. Poulikakos, PhD Assistant Professor Department of Oncological Sciences Department of Dermatology The Tisch Cancer Institute Icahn School of Medicine at Mount Sinai

Dr. Poulikakos

Poulikos I. Poulikakos, PhD
Assistant Professor
Department of Oncological Sciences
Department of Dermatology
The Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai

MedicalResearch.com: What is the background for this study?

Response: Mutations in the oncoprotein kinase BRAF are found in about 8% of human tumors, including more than 50% of melanomas. Small molecule RAF inhibitors prolonged survival of melanoma patients with mutant-BRAF tumors, but resistance limits their effectiveness. Further, RAF inhibitors showed only modest efficacy in patients with colorectal and thyroid mutant-BRAF tumors. Previous studies have suggested that the complex biochemical mechanisms of action of RAF inhibitors account for both sensitivity and major mechanisms of resistance to these drugs. Recently, a number of next generation RAF inhibitors have entered preclinical or clinical development, but the most appropriate clinical context for their use remained elusive.

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Effect of Centralization on Health Disparities in Lung and Bladder Cancer Surgery

MedicalResearch.com Interview with:

Emanuela Taioli MD PhD Professor, Population Health Science and Policy, and Thoracic Surgery Director, Institute for Translational Epidemiology Director, Center for the Study of Thoracic Diseases Outcome Director, Division of Social Epidemiology Icahn Medical Institute, New York, NY 10029

Dr. Taioli

Emanuela Taioli MD PhD
Professor, Population Health Science and Policy, and Thoracic Surgery
Director, Institute for Translational Epidemiology
Director, Center for the Study of Thoracic Diseases Outcome
Director, Division of Social Epidemiology
Icahn Medical Institute,
New York, NY 10029 

MedicalResearch.com: What is the background for this study?

Response: Extensive literature documenting the relationship between hospital volume and clinical outcomes has resulted in the centralization of cancer care advocating patients to seek cancer surgical procedures at high-volume (HV) hospitals. Lung resection and cystectomy have been specifically recommended for centralization, but improvements in outcomes are not shared equally among racial groups. It has also been reported that black patients more commonly undergo surgery at low-volume and lower-quality hospitals, despite living in close proximity to higher quality hospitals.

We investigated the effects of centralization on HV hospital utilization and surgical outcomes for lung (n = 28,047 White; n = 2,638 Black) and bladder (n = 7,593 White; n = 567 Black) cancer patients over a 15 year time span (1997-2011) in New York State. We hypothesized that centralization has improved utilization of HV hospitals and outcomes for both black and white patients, but significant disparities remain between black and white patients.

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Diabetes Drug Reverses Aging Medium That Promotes Melanoma

MedicalResearch.com Interview with:

Reeti Behera, Ph.D. Postdoctoral fellow in the Weeraratna lab The Wistar Institute Philadelphia PA

Dr. Behera

Reeti Behera, Ph.D.
Postdoctoral fellow in the Weeraratna lab
The Wistar Institute
Philadelphia PA

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Malignant melanoma is an aggressive disease and is the cause of the majority of skin cancer deaths. In particular, older individuals have a much poorer prognosis for melanoma and are more resistant to targeted therapy than compared to young individuals. A recently published study from our lab has shown that age-related changes in secreted factors in the microenvironment can drive melanoma progression and therapy resistance.

Klotho is a protein whose expression levels decreases with aging. In this study, we have shown that a decrease in klotho levels in the aged microenvironment drives melanoma aggression and therapy resistance by promoting the oncogenic signaling pathway Wnt5A. We also have shown that reconstituting klotho levels in the aged microenvironment by using rosiglitazone, an FDA-approved drug used to treat diabetes, can reduce tumor burden in aged mice. We also show that Klotho expression is decreased in therapy-resistant melanoma tumors. Reconstituting klotho levels in therapy-resistant melanoma cells by treating with rosiglitazone can inhibit Wnt5A levels and MAPK pathway. We also show that rosiglitazone can significantly decrease therapy-resistant tumor burden in the aged mice, but not in the young.

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False Positive Mammograms Can Lead Women To Delay or Skip Next Exam

MedicalResearch.com Interview with:

Mammogram showing small lesion - Wikipedia

Mammogram showing small lesion
– Wikipedia

Firas Dabbous, PhD
Manager, Patient Centered Outcomes Research
Russell Institute for Research & Innovation
Advocate Lutheran General Hospital
Park Ridge, IL 

MedicalResearch.com: What is the background for this study?

Response: When women are told that there is something abnormal on their screening mammogram that can cause stress and worry while undergoing additional testing, even when they are later told that there is nothing wrong. We wanted to know if receiving a false positive screening mammogram would cause women to think twice before getting their next screening mammogram, and maybe delay coming back for their next screen. This is important because patients who have a false positive experience may have higher chance to develop breast cancer at a later point in time. Therefore, it is important to understand their screening patterns to better educate and inform them about the importance of adhering to mammography guidelines and emphasize the importance of returning on schedule for their next screens.

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ER-beta May Identify Breast Cancer Patients For Whom Chemotherapy is Sufficient

MedicalResearch.com Interview with:
Helena Jernström, PhD
Associate Professor in Experimental Oncology
Study Coordinator for Graduate studies Division of Oncology and Pathology
Coordinator of the programmes in statistics and epidemiology for doctoral students at the Medical Faculty, Lund University
Division of Oncology and Pathology, Department of Clinical Sciences, Lund
Lund University Cancer Center/Kamprad
Lund, Sweden

MedicalResearch.com: What is the background for this study?

Response: There is a need for better predictive markers to guide selection of therapy in breast cancer patients. Estrogen receptor beta (ER-beta) may confer prognostic information beyond what is currently obtained by the established clinical markers, including ER-alpha, which is routinely evaluated.

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Novel microRNA Regulatory Network Has Important Therapeutic Implications in Rhabdomyosarcoma

MedicalResearch.com Interview with:
Riccardo Taulli, PhD
Assistant Professor of Biochemistry
Dept. of Oncology, University of Turin
Via Santena 5, 10126
Torino, Italy

MedicalResearch.com: What is the background for this study?

Response: Rhabdomyosarcoma is a muscle-derived pediatric cancer for which therapeutic options have not improved significantly over the past decades, especially for its metastatic form. MicroRNAs are small regulatory molecules that control gene expression at the post-transcriptional level, fine tuning a wide number of cellular mechanisms, processes and behaviors. In our work, we underwent a large microRNA isolation and sequencing effort using human samples of the three major rhabdomyosarcoma subtypes, along with cell lines and normal muscle, to identify novel molecular circuits with therapeutic potential.
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President of AACR Discusses Sixth Annual Cancer Progress Report

MedicalResearch.com Interview with:

Nancy Davidson, MD President of the American Association for Cancer Research (AACR) and Director, University of Pittsburgh Cancer Institute

Dr. Nancy Davidson

Nancy Davidson, MD
President of the American Association for Cancer Research (AACR) and
Director,  Cancer Institute
University of Pittsburgh

Dr. Davidson discusses the 2016 AACR Cancer Progress Report. “The report serves as an educational document for both Congress and the public, alike. The report is a call to action, designed to urge Congress and the American public to stand firm in their commitment to the conquest of cancer”.

MedicalResearch.com: What is the background and goals for this report?

Dr. Davidson:

  • This is the sixth edition of our annual Cancer Progress Report.
  •  The annual report is the cornerstone of the AACR’s educational and advocacy efforts:
  • The report outlines efforts to increase public and Congressional understanding of cancer and the importance of cancer research to public health and
  • Efforts to advocate for increased federal funding for the NIH, NCI, FDA, and other federal agencies that are vital for fueling progress against cancer
  • The first report was written in 2011, the year that marked the 40th anniversary of the signing of the National Cancer Act of 1971, to commemorate the advances in cancer research that had been made to date and to paint a picture of where the science was leading us.

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RANK signaling-blockade reduces breast cancer recurrence by inducing tumor cell differentiation

MedicalResearch.com Interview with:

Eva Gonzalez Suarez, PhD Group Leader Transformation and Metastasis lab. Cancer Epigenetics and Biology Program-PEBC Institut d'Investigació Biomédica de Bellvitge-IDIBELL Hospital Duran i Reynals Avinguda Gran Via de l'Hospitalet, L'Hospitalet de Llobregat-Barcelona-Spain

Dr. Eva Gonzalez Suarez

Eva Gonzalez Suarez, PhD
Group Leader Transformation and Metastasis lab.
Cancer Epigenetics and Biology Program-PEBC
Institut d’Investigació Biomédica de Bellvitge-IDIBELL
Hospital Duran i Reynals Avinguda Gran Via de l’Hospitalet,
L’Hospitalet de Llobregat-Barcelona-Spain

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Thousands of cancer patients worldwide are taking RANKL inhibitors for the management of bone metastasis, based on the key role of RANKL and its receptor, RANK, driving osteoclastogenesis. RANK signaling pathway acts as a paracrine mediator of progesterone in mouse and human mammary epithelium. RANK expression is associated with poor prognosis in breast cancer even though its therapeutic potential remained unknown.

Complementary genetic and pharmacological approaches demonstrate that therapeutic inhibition of RANK signaling drastically reduces the cancer stem cell pool, decreases tumor and metastasis initiation and enhances sensitivity to chemotherapy in mouse models that closely resemble the clinical disease. Mechanistically, genome wide expression analyses showed that anti-RANKL therapy promotes differentiation of tumor cells into milk-producing cells, as observed during pregnancy.

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