Gideon M. Blumenthal

Targeting the PI3K/Akt/mTOR pathway: Effective combinations and clinical considerations

The PI3K/Akt/mTOR pathway is a prototypic survival pathway that is constitutively activated in many types of cancer. Mechanisms for pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, and exposure to carcinogens. Once activated, signaling through Akt can be propagated to a diverse array of substrates, including mTOR, a key regulator of protein translation. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Moreover, activation of the Akt/mTOR pathway confers resistance to many types of cancer therapy, and is a poor prognostic factor for many types of cancers. This review will provide an update on the clinical progress of various agents that target the pathway, such as the Akt inhibitors perifosine and PX-866 and mTOR inhibitors (rapamycin, CCI-779, RAD-001) and discuss strategies to combine these pathway inhibitors with conventional chemotherapy, radiotherapy, as well as newer targeted agents. We will also discuss how the complex regulation of the PI3K/Akt/mTOR pathway poses practical issues concerning the design of clinical trials, potential toxicities and criteria for patient selection.

PTEN loss in the continuum of common cancers, rare syndromes and mouse models

PTEN is among the most frequently inactivated tumour suppressor genes in sporadic cancer. PTEN has dual protein and lipid phosphatase activity, and its tumour suppressor activity is dependent on its lipid phosphatase activity, which negatively regulates the PI3K–AKT–mTOR pathway. Germline mutations in PTEN have been described in a variety of rare syndromes that are collectively known as the PTEN hamartoma tumour syndromes (PHTS). Cowden syndrome is the best-described syndrome within PHTS, with approximately 80% of patients having germline PTEN mutations. Patients with Cowden syndrome have an increased incidence of cancers of the breast, thyroid and endometrium, which correspond to sporadic tumour types that commonly exhibit somatic PTEN inactivation. Pten deletion in mice leads to Cowden syndrome-like phenotypes, and tissue-specific Pten deletion has provided clues to the role of PTEN mutation and loss in specific tumour types. Studying PTEN in the continuum of rare syndromes, common cancers and mouse models provides insight into the role of PTEN in tumorigenesis and will inform targeted drug development.

PTEN hamartoma tumor syndromes

The PTEN hamartoma tumor syndromes (PHTS) are a collection of rare clinical syndromes characterized by germline mutations of the tumor suppressor PTEN. These syndromes are driven by cellular overgrowth, leading to benign hamartomas in virtually any organ. Cowden syndrome (CS), the prototypic PHTS syndrome, is associated with increased susceptibility to breast, thyroid, and endometrial cancer. PTEN is located on chromosome 10q22–23 and negatively regulates the prosurvival PI3K/Akt/mTOR pathway through its lipid phosphatase activity. Loss of PTEN activates this pathway and leads to increased cellular growth, migration, proliferation, and survival. Clinical management of patients with PHTS, particularly those with CS, should include early and frequent screening, surveillance, and preventive care for associated malignancies. Concomitant with improved understanding of the biology of PTEN and the PI3K/Akt/mTOR pathway, inhibitors of this pathway are being developed as anticancer agents. These medications could have applications for patients with PHTS, for whom no medical options currently exist.

Differentiation therapy in poor risk myeloid malignancies: Results of a dose finding study of the combination bryostatin-1 and GM-CSF

PURPOSE Pharmacologic differentiating agents have had relatively limited clinical success outside of the use of ATRA in acute promyelocytic leukemia and DNA methyltransferase inhibitors in myelodysplastic syndromes. The differentiating effects of such agents can be enhanced in combination with lineage-specific growth factors. We developed a dose finding trial to assess toxicity, differentiating activity, and clinical impact of the combination of bryostatin-1 and GM-CSF. EXPERIMENTAL DESIGN Patients with poor risk myeloid malignancies were eligible to enroll in a dose finding study of continuous infusion bryostatin-1 combined with a fixed dose of daily GM-CSF. Toxicities were graded per NCI CTC version 2.0 and pharmacokinetic and correlative study samples were obtained to assess the combinations clinical and biologic differentiating effects. RESULTS Thirty-two patients were treated with the combination therapy and the dose determined to be most suitable for study in a larger trial was continuous infusion broystatin-1 at 16μg/m(2) for 14 days and subcutaneous GM-CSF at 125μg/m(2) daily for 14 days every 28 days. Arthralgias and myalgias limited further dose escalation. Clinically, the combination impacted differentiation with improvement of absolute neutrophil counts (p=0.0001) in the majority of patients. Interestingly, there were two objective clinical responses, including a CR after a single cycle. Both the bryostatin-1 plasma concentrations and the correlative studies supported biologic activity of the combination at the doses where clinical responses were observed. CONCLUSIONS Combining growth factors with pharmacologic differentiating agents may increase their clinical effectiveness and further studies should focus on such combinations.

Approvals in 2016: the march of the checkpoint inhibitors

In 2016, FDA Oncology approved five new molecular entities and 17 efficacy supplements, including six accelerated approvals, 17 priority reviews, and 11 approvals of breakthrough-designated therapies. The FDA also approved five companion diagnostics, including a liquid biopsy test. One new anti-PD-L1 antibody was approved, along with six supplementary approvals of anti-PD-1/PD-L1 antibodies.

Germline PTEN Mutations As a Cause of Early-Onset Endometrial Cancer

TO THE EDITOR: In the article by Lu et al, 1 the investigators conducted a prospective assessment of the prevalence of Lynch syndrome in women diagnosed with endometrial cancer before age 50 years. Although they identified germline Lynch syndrome–associated mutations in 9% of their patient population, their data also suggest that for 91% of patients with early-onset endometrial cancer, the genetic basis is unclear. One genetic condition that could contribute is Cowden syndrome (CS), which is another inherited cancer susceptibility syndrome in which early endometrial cancer can occur. CS is characterized by germline mutations in the tumor suppressor PTEN that is located on chromosome 10q23.3. Loss of PTEN increases activation of the Akt/mTOR pathway, increases tumorigenesis in many organs in preclinical studies (including the uterus), and is a poor prognostic factor for many types of cancer. Germline mutations in PTEN are associated with a number of hamartomatous syndromes, of which CS is the prototype. CS patients develop thyroid, breast, and endometrial cancers at an earlier age than the general population, and have an overall increased incidence of these cancers compared with the general population. In a young woman diagnosed with endometrial cancer, a thorough history and physical examination evaluating signs of CS such as macrocephaly, mucocutaneous lesions (ie, facial trichilemmomas, acral keratoses, papillomatous lesions, or mucosal lesions) should be performed. If a patient meets established clinical criteria for CS, 2 or has a family member diagnosed with CS, referral for genetic testing and sequencing for germline mutation of PTEN should be considered. Although Lynch syndrome and CS can independently contribute to early-onset endometrial cancer, defects in mismatch repair (MMR), microsatellite instability (MSI), and PTEN mutations might be etiologically related. For example, in a population-based study of patients with sporadic endometrial cancer, 3 tumors with MSI had a higher frequency of PTEN mutations. Patients whose tumors harbored MSI and PTEN mutations were more likely to be diagnosed at an advanced stage and exhibited a worse prognosis. Zhou et al 4 demonstrated that a high frequency of somaticPTEN mutations, especially

Current and Future Management of Malignant Mesothelioma: A Consensus Report from the National Cancer Institute Thoracic Malignancy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation

&NA; On March 28–29, 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation convened the NCI–International Association for the Study of Lung Cancer–Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists, and the U.S. Food and Drug Administration to focus on the development of clinical trials for patients in whom malignant pleural mesothelioma has been diagnosed. In light of the discovery of new cancer targets affecting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least two or three practice‐changing multimodality clinical trials to be conducted through NCIs National Clinical Trials Network.