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Tuesday, February 18, 2020

A team of researchers at the University of Arizona Cancer Center is developing new strategies to prevent and reduce the risk of squamous cell carcinoma, the second most-common form of non-melanoma skin cancer. Skin cancer is the most common malignancy worldwide, and one in three new cancers diagnosed is a form of skin cancer, according to the Skin Cancer Foundation. This amounts to about 5 million non-melanoma skin cancers in the U.S. each year.

Clara Curiel-Lewandrowski, MD, Director of the Cutaneous Oncology Program and Co-Director of the Skin Cancer Institute at the Cancer Center, is principal investigator for a 5-year grant from the National Cancer Institute.

The Program Project Grant will assess, in animal models and human studies, the importance of a novel immune protein known as TLR4, which is modulated by solar ultraviolet radiation. The second focus of the grant includes characterization of a cascade of messages within skin cells recently discovered by the team that are found to promote development of skin cancer after exposure to sunlight. An impactful aspect of the research relates to the formulation and testing of topical drugs—lotions and creams, for example—that effectively can inhibit the action of these proteins ultimately to prevent squamous cell carcinoma formation.

“We are one of the few institutions that has mastered both experimental and clinical studies that effectively mimic the effect of sunlight,” Curiel-Lewandrowski said. “These models allow us to test drugs that can reproducibly and accurately stop or reverse the cellular damage caused by the sun through pilot and phase I clinical trials.

“This highly integrated and translational research-based program project emphasizes the importance of a multidisciplinary and precision medicine approach for the prevention of squamous cell carcinoma of the skin,” Curiel-Lewandrowski continued. “These discoveries also can serve as a model to prevent other epithelial malignancies.”


Tuesday, February 18, 2020

The Cutaneous Oncology Program at the George Washington University (GW) Cancer Center was selected as the first global site for a clinical trial for patients with high-risk cutaneous squamous cell carcinoma. This designation highlights the GW Cancer Center's growing regional and global reputation for treating patients with advanced squamous cell carcinoma, the second most common form of skin cancer behind basal cell carcinoma. The study will examine outcomes for patients treated with cemiplimab—an immunotherapy treatment—prior to surgery and radiation therapy.

In June 2019, the GW Cancer Center was selected as the first global site for a related clinical trial on the effectiveness of cemiplimab given after primary surgery and radiation therapy. This new study will focus on the impact of cemiplimab on tumors prior to surgery, with the goal to help shrink the tumor and potentially prevent the cancer from returning or metastasizing. Preliminary results from a similar trial at MD Anderson Cancer Center showed promising responses to pre-surgical checkpoint inhibitors in patients with advanced cutaneous squamous cell carcinoma of the head and neck.

"By being selected as the first global site for not one, but two clinical trials in 2019, we are continuing to grow our reputation as one of the most innovative programs for patients with advanced cutaneous squamous cell carcinoma," said Vishal A. Patel, MD, FAAD, FACMS, director of the Cutaneous Oncology Program at the GW Cancer Center and principal investigator of the study. "Our growth means even more patients in our region will have access to the latest potentially promising treatments and therapies."

Study Details

The phase II trial is intended to investigate the safety and effectiveness of cemiplimab in helping reduce the size of tumors and prevent recurrence in high risk cutaneous squamous cell carcinoma, particularly when given early. The study, currently only available at the GW Cancer Center, is estimated to enroll over 75 participants.

"This clinical trial fits clearly within our mission to drive transformational research and personalized therapy," said Eduardo M. Sotomayor, MD, Dr. Cyrus Katzen Family Director of the GW Cancer Center and Professor of Medicine at the GW School of Medicine and Health Sciences. "Our role as an academic cancer center means we are uniquely positioned to get the latest therapies from bench to bedside, and expanding our clinical trial offerings highlights our commitment to advancing both cancer research and patient care."

Cemiplimab was approved by the FDA in September 2018 as cemiplimab-rwlc to treat patients with metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation. The immunotherapy treatment is a fully human monoclonal antibody targeting the immune checkpoint receptor PD-1 and was the first treatment approved and available in advanced cutaneous squamous cell carcinoma in the U.S. Current treatment options for the disease include surgery, such as Mohs micrographic surgery, radiation therapy, and systemic chemotherapy for metastatic disease.

"Clinical investigations like this one are critical to expanding the treatment options available to patients," said Mitchell Smith, MD, PhD, Associate Center Director for Clinical Investigations at the GW Cancer Center. "By examining neoadjuvant applications of immunotherapy drugs like cemiplimab, the hope is that patients will be able to be treated with less-invasive surgeries or avoid surgery altogether."

The potential use of cemiplimab in neoadjuvant cutaneous squamous cell carcinoma is investigational, and its safety and efficacy have not been evaluated by any regulatory authority for this use.

Tuesday, February 18, 2020

Researchers at the University of Turku, Turku University Central Hospital, and Western Cancer Center (FICAN West) have discovered a new RNA molecule, PRECSIT, which regulates the growth and invasion of squamous cell carcinoma of the skin (Am J Pathol 2020;190(2)). In the future, PRECSIT could potentially serve as a new marker for the detection of rapidly advancing or spreading squamous cell carcinoma and as a target for new therapies.

Skin cancers are the most common cancers in the world and their incidence is increasing. Squamous cell carcinoma is the most common metastatic skin cancer and its incidence is increasing worldwide. Long-term exposure to the sun's ultraviolet radiation is the most important risk factor for the development of this type of cancer.

Squamous cell carcinoma of the skin is characterized by a significant gene mutation burden of cancer cells resulting from long-term exposure to the sun's ultraviolet radiation. Several gene mutations predisposing to skin cancer are known, but the importance of non-coding RNA molecules of the so-called dark side of the genome in the development of squamous cell carcinoma is still unclear, noted Veli-Matti Kähäri, MD, PhD, Professor in the Department of Dermatology at the University of Turku.

The majority of the human genome contains genes that do not produce protein, but their role as regulators of cellular functions is still essential. Long non-coding RNAs are a largely unknown set of RNAs and recent studies have found that they play a role in regulating signaling pathways, particularly in cancer, said researcher Minna Piipponen, PhD, one of the authors of the study.

Thus, RNA molecules could be utilized in cancer diagnostics as specific marker molecules and as targets for new therapies.

PRECSIT Regulates Growth, Spread of SCC

The study found that expression of a new long non-coding RNA in cancer cells of squamous cell carcinoma was elevated compared to healthy skin. The study also showed that expression of PRECSIT is regulated by the tumor suppressor gene p53, which is inactivated by mutations in most squamous cell carcinomas. The researchers also discovered that PRECSIT promotes the invasion of cancer cells by increasing the production of extracellular matrix cleaving proteolytic enzymes via the STAT3 signaling pathway.

Based on its expression and mechanism of action, this long non-coding RNA was named PRECSIT (p53 regulated carcinoma-associated STAT3-activating long intergenic non-protein coding transcript).

Long non-coding RNAs are currently a hot topic in cancer research worldwide as they could potentially be used as new biomarkers and specific therapeutic targets in different cancers. PRECSIT provides new insight into the role of long non-coding RNA molecules in the progression of squamous cell carcinoma, Piipponen concluded.


Wednesday, February 12, 2020

Radionuclide therapy has proven successful in delaying the growth of disseminated tumor cells (DTCs) in early-stage breast cancer in a small animal model, suggesting its use as a potential adjuvant therapy for delaying the proliferation of DTCs. As reported in the January issue of the Journal of Nuclear Medicine (2019; doi: 10.2967/jnumed.119.227835), the alpha-particle-emitting radiopharmaceutical 223RaCl2 not only impacts cells directly hit by radiation, but also has significant effects on cells outside of the radiation field (i.e., bystander cells).

Breast cancer is the most common cancer diagnosed in women in the U.S. While survival rates for women are high, approximately 20 percent of 5-year survivors ultimately develop metastatic disease 5-10 years after treatment. The formation of metastases involves circulating tumor cells that shed from the primary tumor and gain access to the circulatory system. These DTCs may sustain active proliferation and develop into macrometastases or may remain dormant for years before becoming active.

"With a renewed interest in therapy with alpha-particle emitters and their potential for sterilizing DTCs, our study sought to determine whether bystander effects play a role in 223RaCl2 therapy and, if so, whether they can be leveraged to treat DTCs before disease progression," noted Roger W. Howell, PhD, and co-authors at Rutgers New Jersey Medical School, University of Florida and University of Gothenburg.

In the study, female mice were administered 0, 50, or 600 kBq/kg of 223RaCl2 to create bystander conditions prior to tumor cell inoculation. After 24 hours, mice were inoculated with either estrogen receptor-positive human breast cancer cells or triple-negative (estrogen receptor-negative, progesterone receptor-negative, and HER2 -negative) human breast cancer cells into the tibial marrow compartment. Bioluminescence intensity of the inoculated tumor cell populations was measured on day one and weekly thereafter.

Tumor burden analysis revealed that DTCs were present both within and beyond the range of the alpha particles emitted from 223RaCl2 in both types of breast cancer cells. Growth delays were then tracked for each group of breast cancer cells. Estrogen receptor-positive breast cancer cells responded to the 50 and 600 kBq/kg treatments with 7-day and 65-day growth delays, respectively. In contrast, the triple-negative breast cancer cells demonstrated a 10-day growth delay in tumor progression for the 600 kBq/kg group. No significant difference was noted for the triple-negative breast cancer cell group administered 50 kBq/kg when compared to the control group.

"The increased magnitude of the bystander effect in this study suggests that higher injected activities may better sterilize undetected dormant or slow-growing DTCs in the bone marrow microenvironment," said Howell and co-authors. "Thus, 223RaCl2 may potentially be an adjuvant treatment option for select patients at early stages of breast cancer.

They continued, "This study adds to the mounting evidence that radiation-induced bystander effects can play a role in in the design of future treatment plans for radiopharmaceuticals alone or combined with external-beam therapy. Furthermore, the capacity to target specific cells or tissues in a systemic manner may offer advantages over the use of external beams of radiation for eliciting therapeutic bystander responses."


Wednesday, February 12, 2020

Women with early-stage breast cancer who test positive for an inherited genetic variant are not always receiving cancer treatment that follows current guidelines, a new study finds.

An inherited gene can increase risk of developing a second breast cancer, so strategies such as removing a woman's breasts or ovaries are intended to prevent a future cancer. But women who have already been diagnosed with breast cancer must also consider how best to treat the existing tumor.

"Cancer treatment options are increasingly more complex for patients. Patients must consider a myriad of treatment options for the cancer they have and the implications of genetic test results on cancer prevention strategies for themselves and their family members," said Steven J. Katz, MD, MPH, senior author of a study led by the University of Michigan Rogel Cancer Center and Stanford University School of Medicine.

More women are receiving genetic testing when they're diagnosed with early-stage breast cancer, with increasingly more sophisticated tests that include a panel of at least 30 different genes, each carrying different risks for future cancers.

"We found that breast cancer treatment among women who test positive for an inherited genetic mutation is less in line with practice guidelines, in particular for radiation therapy and chemotherapy," said lead study author Allison W. Kurian, MD, MSc, Associate Professor of Medicine and of Health Research and Policy at Stanford.

"It's challenging to integrate genetic testing into breast cancer care," said Kurian. The significance of the results and future impact on the patient's risk vary widely while meanwhile we must focus on eliminating the cancer the patient faces today."

Researchers collected information from the Georgia and California Cancer Registries from 20,568 women diagnosed with early-stage breast cancer and matched it to genetic testing results. All data was linked through an objective third party and deidentified for researchers to analyze. Results are published in JAMA Oncology (2020; doi 10.1001/jamaoncol.2019.6400).

Researchers looked at the characteristics of patients' tumors to assess what the recommended treatment options would be based on standard guidelines. Then they compared actual treatments for women who tested positive for BRCA1 or BRCA2 mutations, which carry the highest risk for additional cancers, those who tested positive for other genes associated with breast cancer, and those whose tests were negative or identified a variant not known to increase breast cancer risk.

They found distinct differences in surgery, radiation, and chemotherapy treatments among women who were positive for an inherited genetic mutation.

Surgery: 66 percent of BRCA-positive patients underwent double mastectomy, compared to 24 percent of patients with a negative genetic test

Radiation: 51 percent of BRCA-positive patients who were candidates for radiation received it, compared to 82 percent of patients with a negative genetic test

Chemotherapy: 38 percent of BRCA-positive patients who were candidates to forgo chemotherapy received it, compared to 30 percent of patients with a negative genetic test

The observed relationship of surgical treatment to genetic test results are in line with guidelines supporting double mastectomy as an effective strategy to prevent future cancer risk. But guidelines do not recommend using genetic testing results to determine whether radiation or chemotherapy are needed to treat the diagnosed cancer.

The gaps in radiation were particularly striking as radiation after lumpectomy is considered key to achieving the best outcome with breast conservation. The researchers propose that some patients may have skipped radiation because they intend to have a mastectomy in the future. Another explanation could be concern about whether radiation would increase cancer risk for these patients.

"We need to understand this gap better, because it could have potential implications on patients' outcomes," said Katz, Professor of General Medicine and of Health Management and Policy at the University of Michigan.

"Our findings should reinforce that physicians who treat cancer need to be increasingly attentive to the clinical implications of genetic testing after diagnosis. Test results must be optimally integrated into the patient's treatment to manage her cancer today and her risk in the future," Kurian said.