AACR, Author Interviews, Boehringer Ingelheim, Cancer Research / 13.05.2020

MedicalResearch.com Interview with: Dr. Udai Banerji, MD The Institute of Cancer Research and The Royal Marsden MedicalResearch.com: What is the background for this study? Response: Not only have I been working in the RAS mutations oncology world for a while, but I also have prior preclinical experience working with VS-6766 (RAF/MEK inhibitor) and defactinib (FAK inhibitor), the two drugs in the Phase 1 study that was presented at the American Association for Cancer Research (AACR) annual medical meeting on April 27th. It is important to know that there is a great significant medical need for novel treatments for KRAS mutant tumors, which are difficult to treat, aggressive, and quite common across advanced solid tumors, including low-grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), resulting in the need for novel treatments in an area of significant medical need. I felt that early signals in preclinical research warranted a clinical trial; so that, combined with my RAS experience, made pursuing the Phase 1 study a clear fit. A clinical trial setting allowed us to explore RAF and RAS inhibitor combinations in multiple tumor trials, which was our aim. The data presented at AACR convey safety and dose response results from the dose-escalation portion and expansion cohorts from an open-label, investigator-initiated Phase 1 study evaluating the combination of VS-6766 (RAF/MEK inhibitor) and defactinib (FAK inhibitor) therapy in patients with LGSOC and KRAS mutant NSCLC. The introductory data described in the study suggest that a novel intermittent dosing schedule of RAF/MEK and FAK inhibitor combination therapy has promising clinical activity in patients with KRAS mutant LGSOC and KRASG12V mutant NSCLC, including patients formerly treated with a MEK inhibitor. Expansion cohorts remain ongoing.  (more…)
AACR, Author Interviews, Biomarkers, Cancer Research, MD Anderson, Pharmaceutical Companies / 09.05.2020

MedicalResearch.com Interview with: David S Hong, M.D MD Anderson Department of Investigational Cancer Therapeutics Division of Cancer Medicine University of Texas MedicalResearch.com: What is the background for this study? Response: Larotrectinib is a first-in-class, CNS active, oral TRK inhibitor exclusively designed to treat tumors with an NTRK gene fusion and does not have secondary targets. In previous presentations and published in The Lancet Oncology, larotrectinib demonstrated robust tumor-agnostic efficacy in an integrated dataset of 159 adult and pediatric patients with TRK fusion cancer across three clinical trials (Feb 2019 data cut-off date). In these studies, the objective response rate (ORR), according to investigator assessment, was 79% (95% confidence interval [CI], 72 – 85%), with a complete response rate of 16%. In this analysis presented at AACR 2020, we sought to evaluate the outcomes in patients from the integrated data set based on different baseline characteristics, including prior lines of therapy and Eastern Cooperative Oncology Group (ECOG) performance status. ECOG measures how the disease impacts a patient. ECOG describes a patient’s level of functioning with a numbering scale (0-5) so physicians can uniformly describe a patient’s ability to care for themselves, daily activity and physical activity (selfcare, walking, working, etc). (more…)
AACR, Author Interviews, Bayer, Cancer Research / 08.05.2020

MedicalResearch.com Interview with: David S Hong, M.D Department of Investigational Cancer Therapeutics Division of Cancer Medicine MD Anderson, University of Texas MedicalResearch.com: What is the background for this study? Response: Larotrectinib is a first-in-class, CNS active, oral TRK inhibitor exclusively designed to treat tumors with an NTRK gene fusion and does not have secondary targets. In previous presentations and published in The Lancet Oncology, larotrectinib demonstrated tumor-agnostic efficacy in an integrated dataset of 159 adult and pediatric patients with TRK fusion cancer across three clinical trials (Feb 2019 data cut-off date). In these studies, the objective response rate (ORR), according to investigator assessment, was 79% (95% confidence interval [CI], 72 – 85%), with a complete response rate of 16%. A variety of NTRK genes have been identified in various tumor types including fusions and non-fusions (e.g., amplifications, rearrangements, deletions, slice variants). In the analysis presented at AACR 2020, we sought to evaluate this pooled data to determine the efficacy of larotrectinib in patients with non-fusion alterations in NTRK genes.  (more…)
AACR, Author Interviews, Cancer Research, Genetic Research, Yale / 27.02.2020

MedicalResearch.com Interview with: Lajos Pusztai, M.D, D.Phil. Professor of Medicine Director, Breast Cancer Translational Research Co-Director, Yale Cancer Center Genetics and Genomics Program Yale Cancer Center Yale School of Medicine New Haven, CT 05620  MedicalResearch.com: What is the background for this study? Response: We analyzed breast cancer tissues obtained before any therapy and the same cancers after 20 weeks of chemotherapy. This setting is ideal to find out what genomic changes have occurred in cancers that survived therapy. Due to the paucity of such specimens few other studies exist in this space. (more…)
AACR, Author Interviews, Cancer Research, Ovarian Cancer / 23.12.2019

MedicalResearch.com Interview with: Rugang Zhang, Ph.D Professor & Co-Leader, Gene Expression & Regulation Program Deputy Director, The Wistar Institute Cancer Center MedicalResearch.com: What is the background for this study? Response: Although the majority of epithelial ovarian cancer (EOC) patients initially respond well to platinum therapy, relapse ultimately occurs, which remains a major challenge in the clinical management of EOC. Substantial evidence suggests that cancer stem-like cells (CSC) contribute to chemotherapy resistance and elimination of CSC prevents the therapeutic relapse including in EOCs. Thus, therapeutic elimination of EOC CSCs represents a promising approach to achieve a durable therapeutic outcome by preventing chemotherapy resistance. Platinum-based chemotherapies are known to induce senescence that limits the propagation of cells subjected to insults such as cancer chemotherapeutics. In contrast to apoptosis, senescent cells remain viable. Senescent cells secrete a plethora of pro-inflammatory cytokines and chemokines, which is termed senescence-associated secretory phenotype (SASP). Therapy-induced inflammation promotes tumor progression and therapy resistance, and the SASP is known to promote cancer stem-like cells. However, clinically applicable approaches to target stemness associated with therapy-induced senescence remain to be explored.  (more…)
AACR, Author Interviews, Melanoma / 20.10.2019

MedicalResearch.com Interview with: Qing Chen, M.D., Ph.D. Assistant Professor, Immunology, Microenvironment & Metastasis Program Scientific Director, Imaging Facility The Wistar Institute MedicalResearch.com: What is the background for this study? Response: We are focusing on how a specific type of brain cells, astrocytes, helps the cancer cells from melanoma and breast cancer to form metastatic lesions.  (more…)
AACR, Author Interviews, Pancreatic / 24.09.2019

MedicalResearch.com Interview with: Hadas Reuveni, PhD VP of Research and Development Kitov Pharma MedicalResearch.com: What is the background for this study? Response: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide. Current treatments fail to provide patients with an effective and long-lasting response, mostly given to the nature of the tumor microenvironment which hinders drug accessibility, the late stage on diagnosis and the rapid upregulation of compensatory alternative signaling pathways by the tumor cells that lead to cancer drug resistance. Two of the major parallel pathways regulating tumor survival and metastasis as well as the crosstalk of the tumor and its microenvironment are mediated by insulin receptor substrate (IRS) 1 and 2, and by the signal transducer and activator of transcription 3 (STAT3). Both IRS1 and STAT3 have been shown to play a significant role in development of drug resistance by tumor cells. NT219, the focus of the current study, is a small molecule that presents a new concept in cancer therapy. NT219 represents a new family of novel compounds acting as a dual inhibitor of both IRS1/2 and STAT3 signaling both directly in the tumor and its microenvironment. We have previously shown that simultaneous inhibition of these two pathways is crucial to overcome drug resistance, and to prolong the positive response of the anti-cancer activity of approved cancer drugs. NT219 targets IRS1/2 for degradation using a unique mechanism, supported by a feed-forward decrease in IRS gene expression. A long-term suppression of both IRS and STAT3 by NT-219 has been demonstrated in previous preclinical studies, which lasted days following removal of NT219 from the cancer cells, assuring a strong and prolonged anti-cancer activity. This study was designed to investigate the efficacy of NT219 at overcoming drug resistance to several approved oncology therapies using patient-derived xenograft (PDX) models of KRAS mutant pancreatic cancer, as well as to validate NT219's mechanism of action and optimal dose regimen.  (more…)
AACR, Author Interviews, CT Scanning, Lung Cancer / 28.06.2019

MedicalResearch.com Interview with: Barbara Nemesure, PhD Professor, Department of Family, Population and Preventive Medicine Division Head, Epidemiology and Biostatistics Director, Cancer Prevention and Control Program Director, Lung Cancer Program, Stony Brook Cancer Center Renaissance School of Medicine Stony Brook University    MedicalResearch.com: What is the background for this study? What are the main findings? Response: Lung cancer is the most common cause of cancer death, claiming the lives of more than 150,000 people in the United States each year. While lung nodules are not uncommon, it has remained a challenge to differentiate those that will progress to cancer and those that will remain benign. Although numerous risk prediction models for lung cancer have been developed over the past 2 decades, the majority have been based on retrospective analyses or high risk groups with a strong history of tobacco use. To date, there have been a limited number of large-scale, prospective studies evaluating risk that a nodule will convert to cancer in the general population. This investigation aimed to construct a population-based risk prediction model of incident lung cancer for patients found to have a lung nodule on initial CT scan. The derived model was determined to have high accuracy for predicting nodule progression to cancer and identified a combination of clinical and radiologic predictors including age, smoking history (pack-years), a personal history of cancer, the presence of chronic obstructive pulmonary disease (COPD), and nodule features such as size, presence of spiculation and ground glass opacity type. When compared to patients in the low risk category, those defined as high risk had more than 14 times the risk of developing lung cancer. Quantification of reliable risk scores has high clinical utility, enabling physicians to better stratify treatment plans for their patients.      (more…)
Author Interviews, Immunotherapy, Pancreatic / 14.11.2018

MedicalResearch.com Interview with: Dr James Kuo, MBBS Medical oncologist and Deputy Medical Director Scientia Clinical Research Sydney, Australia MedicalResearch.com: What is the background for this study? What are the main findings?  Response: Immune checkpoint inhibitors (ICI) that have seen success in the treatment of patients with various tumour types have not been as effective in patients with metastatic pancreatic cancer and therefore immune-therapeutic agents of novel mechanism of action, in particular in combination with existing ICI, need to be investigated. This study set out to test the safety and efficacy of pixatimod, a novel immunomodulatory agent, in combination with nivolumab, firstly in the dose escalation cohorts in patients with any solid tumour for the maximal tolerable dose, and then using this dose to further treat an expansion cohort of patients with pancreatic cancer. Altogether 16 patients had received the combination and in 10 patients in whom treatment response was evaluable, 4 patients experienced a clinical benefit and continued treatment in the trial, with 1 patient having a significant partial response now treated for 48 weeks. Interestingly, all these 4 patients had metastatic colorectal cancer. Side effect profile has been consistent with other immunotherapeutic agent combination and in the patients who had clinical benefit, no treatment related side effects were observed.  (more…)
Alcohol, Author Interviews, Prostate Cancer / 23.08.2018

MedicalResearch.com Interview with: Emma H. Allott, PhD Research Assistant Professor of Nutrition UNC GILLINGS SCHOOL OF GLOBAL PUBLIC HEALTH University of North Carolina, Chapel Hill  MedicalResearch.com: What is the background for this study? What are the main findings? Response: Prostate cancer development may span decades. In addition, the prostate grows rapidly during puberty and therefore may be particularly susceptible to dietary or lifestyle factors during this time. Our study found that heavier alcohol intake earlier in life, as well as higher cumulative alcohol intake across the lifespan, was associated with an increased odds of being diagnosed with an aggressive (clinically significant) prostate cancer in later life. However, current alcohol intake at the time of prostate cancer diagnosis was unrelated to tumor aggressiveness. (more…)
AACR, Author Interviews, Cancer Research, Imperial College, Kidney Disease / 20.08.2018

MedicalResearch.com Interview with: Dr. David C. Muller PhD Faculty of Medicine, School of Public Health Research Fellow in Epidemiology and Biostatistics Imperial College, London MedicalResearch.com: What is the background for this study? What are the main findings? Response: Our colleagues in the U.S. have been working on KIM-1 for years, particularly in the context of chronic kidney disease. Recently they found that KIM-1 is also elevated at the time of diagnosis of kidney cancer. We wanted to see if KIM-1 concentrations could predict the chances of a future diagnosis of kidney cancer. We found that KIM-1 was a strong predictor of being diagnosis with kidney cancer in the next 5 years. We also found that higher pre-diagnostic KIM-1 was associated with worse survival after diagnosis.  (more…)
AACR, Author Interviews, Biomarkers, Brigham & Women's - Harvard, Cancer Research, Immunotherapy, Neurology, Radiology / 01.05.2017

MedicalResearch.com Interview with: 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. (more…)
AACR, Author Interviews, Cancer Research / 21.09.2016

MedicalResearch.com Interview with: 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.
(more…)
AACR, Author Interviews, Biomarkers, Breast Cancer / 15.09.2016

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 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. (more…)
AACR, Author Interviews, Cancer Research, Prostate Cancer / 04.09.2016

MedicalResearch.com Interview with:  

Ilaria Stura PhD

Università degli Studi di Torino Turin, Piedmont, Italy

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

Response: Man has always tried to predict the future, especially to prevent catastrophes, diseases and death. In this case, we want to prevent the ‘personal catastrophe’, i.e. the spread of the disease (recurrence of prostate cancer) in the patient. Our work therefore belongs to the so-called ‘personalized medicine’, a very important and innovative clinical approach.

In particular this study may potentially improve the quality of life of the patients and help the clinicians, since it could give valuable information to the urologist, for example reporting that the growth velocity of the tumor is increasing and that a relapse is expected within few months. With this information, the clinician could chose the best therapy for the patient (e.g. hormone or radio therapy) in order to stop the spread of the disease or, conversely, the use of drugs can be delayed if not necessary. Obviously clinicians already try to do this, based on their experience, but our method provides further confidence in their 'investigation' work, since the algorithm is validated on data coming from a database much larger than his/her personal experience. (more…)
Author Interviews, Cancer Research, Pain Research, Pediatrics / 16.09.2015

Prof. Dr. Holger Lode Clinical Immunology, Pediatrics University of Greifswald, GreifswaldMedicalResearch.com Interview with: Prof. Dr. Holger Lode Clinical Immunology, Pediatrics University of Greifswald, Greifswald Medical Research: What is the background for this study? Response: Neuroblastoma is a cancer in childhood with one of the highest death rates.  Standard treatment is already very intensive. It includes chemotherapy, surgery, radiation, high dose chemotherapy followed by autologous stem cell transplantation. However, the progress made in improving survival rates is still poor. The use of an immune-modulatory treatment with a neuroblastoma specific monoclonal antibody ch14.18 (100 mg/m2 /cycle) in combination with cytokines and 13cis retinoic acid (13 cis RA) has shown benefit for patients with this disease [1].  This antibody targets ganglioside GD2 abundantly expressed on neuroblastoma with limited to no expression on healthy tissue. Low expression of GD2 on pain fibers is associated with an on-target side effect of the treatment, which is the induction of neuropathic pain. Approval of ch14.18 (dinutuximab) for the treatment of children with neuroblastoma has been provided by FDA. In Europe, ch14.18 was not available for a long time. There were several reasons why the antibody in the US could not be given to children in Europe. Therefore a new development of this side of the Atlantic was initiated following the remanufacturing of the antibody in CHO cells [2] (dinutuximab beta) and was made available within clinical trials of the SIOPEN group. The SIOPEN group is a network of leading European pediatric oncology centers to improve outcome for children with neuroblastoma (http://www.siopen.org), similar to the COG (children`s oncology group in the USA; https://www.childrensoncologygroup.org). Following the recloning procedure, ch14.18/CHO was first evaluated for safety in a Phase I study [3], which confirmed the tolerability and showed activity at a dosing regimen of 20 mg/m2 given by 8 hour infusions on 5 consecutive days. Dinutuximab beta is further developed by Apeiron Biologics. The current way to apply 100 mg /m2 / cycle is by 4 short term infusions of 25 mg/m2/day each over 8 hrs on 4 consecutive days. The entire treatment consists of 5 cycles. The drawback is that STI is associated with a high amount of intravenous morphine required to make this treatment tolerable for patients. Also the rate of inflammatory side effects observed is substantial. Clinical observation indicates that if patients treated by STI suffer from pain despite analgesic treatments, a decrease in speed of antibody infusion improves this on target toxicity. Therefore, we hypothesized that significant prolongation of the time of antibody infusion will improve tolerability of that treatment, but at the same time maintains clinical activity and efficacy in high risk neuroblastoma patients. (more…)