Posted 8/1/2017 9:38 AM (GMT -7)
congrats on the great results, out cruisin'! i'm so happy for you! do you by any chance know why percentage your ki value is? if so, there is a clinical trial at princess margaret hospital in toronto (or was, not sure if it's still running)...not sure if you'll be allowed in being from the states, but it's worth a try contacting them and seeing if you qualify. my dad had this small cell/neuroendocrine strain as well but unfortunately his ki was very high (more than 90%) so we weren't even told about the trial.
in my dad's case, he only had one bone met so his MO decided to watch and wait. but a month later the cancer had spread everywhere and my dad didn't get chemo for almost another month after that. by then it was too late because the cancer was just too extensive by that point. that's so great you got access to chemo early and are cancer free now! hopefully others with this strain can gain some optimism and inspiration from that...thank you so much for sharing. when we were researching it was so hard to find others in the same situation.
my sister, husband, brother-in-law and i did TONS of research on this mutation and here are some articles which will hopefully help you (i'm copying and pasting as i sent these to our MO as faxes - he didn't want emails so that's why there are no links but all of these i found online). there is some more stuff i have but just need to find it all...will update here when i do but here are some things for a start. the key really is to have a therapy plan ready and waiting and take action super quickly if one starts to fail. i know we are at the mercy of doctors in these situations and unfortunately for us ours just kept delaying and didn't listen to any of our suggestions or requests to start chemo, do PET scans, do genetic testing etc. i think mayo is for sure the right choice and you're in such a great position right now being cancer free. i hope the below helps in some way:
ROVALPITUZUMAB TESIRINE SHOWS EARLY PROMISE IN SMALL CELL LUNG CANCER 06 June 2016
Rovalpituzumab tesirine (Rova-T or SC16LD6.5; AbbVie), a novel biomarker-specific ‘smart-bomb’ antibody-drug conjugate or ADC targeting the delta-like protein 3 or DLL3 protein, expressed in more than 80% of small-cell lung cancers (SCLC) patient tumors, appears to be safe and shows efficacy in treating patients with advanced SCLC.
Antibody-drug conjugates like rovalpituzumab tesirineare are large molecules in which anticancer drugs are
attached to an antibody. The antibody targets a protein that is abundant on the surface of cancer cells, but is preferably rarely found on healthy cells. Following the attachment of the antibody to the target protein on a cancer cell, the cancer cell internalizes the antibody-drug conjugate. Inside the cancer cell, the cancer drug is released from the antibody where it exerts its cancer-killing effect. In this way, the new trial drug works like a “Trojan horse.”
Because the DLL3 protein is not or rarely expressed in healthy cells the targeted delivery of the novel cancer drugs to cancer cells helps minimizes ‘collateral’ damage to normal – healthy – tissues. In fact, the payload used in the cytotoxic anti-cancer drug in rovalpituzumab tesirine is so potent that it cannot be given systemically as a standalone treatment. However, the studies show that the drug, when attached to an antibody – as an ADC – is relatively safe.
Rovalpituzumab tesirine – Rova-T – comprises of an anti-DLL3 antibody conjugated to a pyrrolobenzodiazepine dimer, a cancer-killing DNA-damaging agent. Pyrrolobenzodiazepines (PBDs) are a class of sequence-selective DNA minor-groove binding crosslinking agents originally discovered in Streptomyces species. The mechanism of action of the PBDs is associated with their ability to form, an adduct in the minor groove, thus interfering with DNA processing.
The early results of a first-in-human clinical trial, presented on Sunday, June 5, by a Memorial Sloan Kettering Cancer Center‘s Charles M. Rudin, MD, PhD, Chief of the Thoracic Oncology Service, at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, held June 3 – 7, 2016 in the McCormick Place in Chicago, Ill, show that patients responded better to the drug when their tumors expressed high levels of delta-like protein 3 (DLL3), the protein Rova-T targets (ASCO abstract LBA8505)
The study shows that Rova-T halted tumor growth in 89% of patients with high level of DLL3 in the tumor and shrank tumors in 39%.
Small-cell Lung Cancer
Each year, an estimated 225,000 Americans will be diagnosed with lung cancer. Small-cell Lung Cancer accounts for approximately 15% of all lung cancers, is particularly aggressive — about two-thirds of patients have extensive-stage disease when they are first diagnosed, and the median survival for these patients is less than a year.
The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.
To date, combination chemotherapy improves the survival of patients with limited-stage disease or extensive-stage disease. While combination chemotherpy of platinum and etoposide, the most widely used standard chemotherapeutic regimen, is curative in only a minority of patients and surgical resection or radiation therapy rarely produces long-term survival because patients with SCLC tend to develop distant metastases, there is a large unmet need.
In the United States, the only Food and Drug Administration (FDA) approved drug for the treatment of SCLC is topotecan (Hycaptin ®; Novartis)
However, despite major advances made during the 1970s and in the 1980s, today, treatment success seems to have reached a plateau and substantial therapeutic advances have lagged far behind this of other cancers.
Rovalpituzumab tesirine – Rova-T – is the first molecularly targeted drug to show antitumor efficacy in SCLC.
“The goal is always to give the right patient the right drug at the right time, but patients with advanced small cell lung cancer have not benefited from any of the new targeted therapies available to patients with other types of cancer,” Rudin explained.
“They desperately need new treatment options, so the ability to predict whether a patient might respond to Rova-T by testing their tumor for overexpression of the DLL3 protein is crucial because it may ultimately help us give this drug to the patients most likely to benefit from it, and avoid giving it to patients who won’t,” he said.
The phase I clinical trial included 74 patients with SCLC that had progressed after at least one course of systemic therapy. Of the 60 evaluable patients treated with doses in the active range of 0.2-0.4 mg/kg, 68% experienced at least stabilization of disease, meaning their cancer did not get worse, and 18% had significant confirmed tumor reductions.
The study included 26 evaluable patients with tumors that overexpressed DLL3. Stable disease was achieved in 89% of these patients; 39% had significant confirmed tumor reductions.
Twelve of the patients whose tumors overexpressed DLL3 received Rova-T as third-line treatment, for which no approved therapy currently exists. Half of these patients had significant tumor reductions, and 92 percent experienced at least stabilization of disease. Four of these patients lived longer than six months, including two who lived for at least 18 months.
Manageable side effects
The side effects from Rova-T were manageable. The most common grade 3+ toxicities considered the results of the study-drug included serial effusion (fluid accumulation around the heart or lungs) in 14% of patients, thrombocytopenia (low platelet count) in 12% of patients and skin rash/reactions (8%). Overall, these adverse events could be easily treated with medications, or, in many cases, resolved without specific interventions.
“We’ve seen too few success in recent years for SCLC, which makes these early signs of efficacy all the more encouraging,” Rudin noted. “Although these results are preliminary, Rova-T seems to be the first targeted therapy to show efficacy in SCLC and we may have identified DLL3 as the first predictive biomarker in this disease.”
The findings of this early-stage first-in-human clinical trial need to be confirmed in larger clinical trials. A single-aim phase II pivotal trial in patients with DLL3-positive SCLC that has worsened despite two prior therapies was launched earlier this year. The researchers are planning other trials designed to evaluate rovalpituzumab tesirine in first line SCLC and other DLL3-espressing neuroendocrine cancers.
“I encourage all oncology physicians and patients to seek out information about clinical trials, as they often give patients the opportunity to receive new drugs and other therapies years before they are more widely available,” Rudin said. “It’s increasingly important to remember that nearly every advance in cancer treatment available today was first evaluated in a clinical trial.”
He added that future clinical trials investigating Rova-T’s efficacy in treating SCLC will generally focus on the subset of patients whose tumors express the DLL3 target.
Memorial Sloan Kettering Cancer Center and other participating trial centers currently have an open Rova-T clinical trial for patients with advanced SCLC who have received at least two prior therapies (NCT02674568). Patients to be enrolled in this pivotal trial will receive Rova-T, as there is no standard third-line treatment to test Rova-T against.
Rudin also noted there are other important lines of research to explore around Rova-T, including how the drug affects the tumor microenvironment, whether it prompts an immune response and if there is a population of patients for whom this drug might not be safe.
A new wave of targeted agents
Commenting on the results of this study, Gregory Masters, MD, FACP, FASCO, an expert in the treatment of lung cancers, noted: “This is another example of a new wave of highly targeted treatments, which deliver anticancer drugs even more precisely to where they needed.”
“These results mark a good, early sign of success against a cancer for which we urgently need better therapy options,” Masters concluded.
Advanced Prostate Cancer Patients May Respond Well to Keytruda Immunotherapy, According to Study
JULY 20, 2016
Immunotherapy with Keytruda (pembrolizumab) may be an effective way to treat advanced-stage prostate cancer, according to a preliminary study conducted by researchers at Oregon Health and Science University (OSHU) Knight Cancer Institute.“It’s pretty remarkable, especially in light of the fact that many people doubted this approach could work at all,” said Dr. Julie Graff in a press release.Graff is the senior author of the study “Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer,” published in the journal Oncotarget.
Keytruda is a monoclonal antibody that blocks the PD-1 receptor on the surface of immune T-cells, allowing them to recognize and destroy tumor cells. The FDA-approved drug has been shown to work well in melanoma and lung cancer but had so far not produced any evidence of anti-tumor activity in prostate cancer.
Researchers administered Keytruda in 10 men with metastatic prostate cancer who had received androgen deprivation therapy or the androgen receptor antagonist Xtandi (enzalutamide) but failed to respond to it.
Three of the 10 men who participated to the trial responded remarkably well to Keytruda treatment. Prostate specific antigens (PSA) in their blood, which is an early measure of treatment response, dropped rapidly and dramatically (from 46, 71, and 2,503 ng/ml respectively, to less than 0.1 ng/ml).
In addition, two of the three men saw their tumors shrink and reported a reduction in cancer-related pain to the point of not needing their opiate pain medication. Finally, the three patients who responded to Keytruda remained free of cancer progression at 30, 55, and 16 weeks of follow-up, respectively.
Drugs currently available to treat prostate cancer rarely result in PSA levels lower than 0.2 ng/ml. “You don’t get responses like this with almost any other treatment,” Graff said.
It is still unclear why only three of the 10 men who participated in the clinical trial responded to treatment with Keytruda, while others showed no signs of clinical benefit. It is not yet possible to conclude that blocking PD-1 signaling can improve survival in men with metastatic prostate cancer, or to predict which patients will respond to treatment.
More research is needed to better understand the mechanisms by which Keytruda reduces prostate cancer and which factors may influence the therapeutic effect of the drug. The team is continuing to monitor the patients enrolled in the clinical trial and have recruited more participants. Future studies are also being planned.
Asian J Androl. 2016 Nov 29. doi: 10.4103/1008-682X.191518. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27905327?dopt=Abstract&utm_source=dlvr.it&utm_medium=twitter
Potential therapeutic effect of epigenetic therapy on treatment-induced neuroendocrine prostate cancer.
Xu X1,2, Huang YH3, Li YJ2, Cohen A2, Li Z4, Squires J2, Zhang W5, Chen XF2, Zhang M1, Huang JT2.
Although adenocarcinomas of the prostate are relatively indolent, some patients with advanced adenocarcinomas show recurrence of treatment-induced neuroendocrine prostate cancer, which is highly aggressive and lethal. Detailed biological features of treatment-induced neuroendocrine prostate cancer have not been characterized owing to limited biopsies/resections and the lack of a cellular model. In this study, we used a unique cellular model (LNCaP/NE1.8) to investigate the potential role of cancer stem cells in treatment-induced neuroendocrine prostate cancer with acquired resistance to hormonal therapy and chemotherapy. We also studied the role of cancer stem cells in enhancing invasion in treatment-induced neuroendocrine prostate cancer cells that recurred after long-term androgen-ablation treatment. Using an in vitro system mimicking clinical androgen-ablation, our results showed that the neuroendocrine-like subclone NE1.8 cells were enriched with cancer stem cells. Compared to parental prostate adenocarcinoma LNCaP cells, NE1.8 cells are more resistant to androgen deprivation therapy and chemotherapeutic agents and show increased cancer cell invasiveness. Results from this study also suggest a potential epigenetic therapeutic strategy using suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, as a chemotherapeutic agent for therapy-resistant treatment-induced neuroendocrine prostate cancer cells to minimize the risk of prostate cancer recurrence and metastasis
Aurora A kinase inhibition and treatment of neuroendocrine prostate cancer
Posted on April 7, 2016 by Sitemaster
A research team in Los Angeles has demonstrated that a protein produced by a cancer gene (the MYCN gene) leads to the development of the often deadly, late-stage form of prostate cancer called neuroendocrine prostate cancer.
The paper describing this research, by Lee et al., was published recently in Cancer Cell, and readers can also get more information from this media release from the University of California, Los Angeles.
Lee et al. have shown that:
N-Myc and AKT1 drive development of neuroendocrine prostate cancer from human prostate epithelium.
Prostate epithelial cells can give rise to neuroendocrine and epithelial cancers.
N-Myc is essential for tumor maintenance in tumors initiated by N-Myc and AKT1.
Destabilization of N-Myc through inhibition of the enzyme aurora A kinase can induce tumor cell death.
They also showed that an experimental drug called CD532, which acts on aurora A kinase, could reduce the size of neuroendocrine prostate cancer tumors that had been implanted in mice by 80 percent.
Dr. Lee is quoted as saying that the research team’s next steps will be to try and identify drugs other than CD532 that may be effective for treating neuroendocrine prostate cancer. This would seem to suggest that CD532 is not, in and of itself, a good candidate for use as a drug in humans. To date, CD532 has only been used in preclinical studies, has not been tested in humans at all, and quite certainly has not been approved by the U.S. Food and Drug Administration as safe and effective for use in humans (for any type of cancer treatment).
A possible new opportunity for treatment of advanced, neuroendocrine forms of prostate cancer? Posted on January 12, 2017
An article by Strosberg et al. in today’s issue of the New England Journal of Medicine has nothing to do with prostate cancer at all; it’s all about a new form of treatment for certain types of advanced midgut cancer — but …
The question it raises is whether, if the drug used in this trial (a drug known as lutetium-177 dotatate or [177Lu]dotatate) is as effective as it seems to have been in the treatment of advanced midgut neuroendocrine cancers, there is reason to at least hope that it might exhibit a high level of efficacy in the treatment of advanced forms of neuroendocrine prostate cancer too — or at least that some other formulation of lutetium-177 delivery system (e.g., 177Lu PMSA conjugates) might have similar level of efficacy.
Just to give you a flavor of the outcomes in the Phase III trial reported in the new article by Strosberg et al., the authors report that, compared to standard therapy with a long-acting form of octerotide (the control group), the combination of long-acting octreotide + [177Lu]dotatate, after 20 months of follow-up:
The estimated rate of progression-free survival was
65.2 percent in the [177Lu]dotatate group
10.8 percent in the control group.
Overall response rates were
18 percent in the [177Lu]dotatate group
3 percent in the control group (P<0.001).
The number of deaths from all causes was
14 in the [177Lu]dotatate group
26 in the control group
Adverse effects associated with treatment included
Grade 3 or 4 neutropenia (1 percent), thrombocytopenia (2 percent), and lymphopenia (9 percent) among patients in the [177Lu]dotatate group
No grade 3 or 4 neutropenia, thrombocytopenia, or lymphopenia among patients in the control group
No evidence of renal toxic effects associated with either form of therapy
Overall survival data from this trial are not yet available, and will require further patient follow-up, but these results are already impressive for the roughly 20 percent of the patients in this trial who did respond well to this new form of treatment.
It seems likely that this trial will lead to the approval of [177Lu]dotatate as a treatment for advanced midgut neuroendocrine cancers here in the USA and potentially elsewhere as well. Such an approval would mean that it would also became available for use (off label) by medical oncologists working with nuclear medicine specialists in the treatment of other forms of neuroendocrine cancer too.
The bigger question will be whether these data stimulate trials of forms of 177Lu in the treatment of neuroendocrine forms of advanced prostate cancer.
Jan 2010:Gleason 8 post-surgery / PSA 4 /PNI
PSA after RP:2
June 2013:Lupron stopped/PSA 0
Jan 2016 Chemical recurrence 0.04
Oct 2016 PSA just over 1
Feb 2017:PSA 0.45. mixed bone lesion T6 spine, surgery for spinal compression. Casodex/Lupron. rad to met & surrounding
High grade neuroendocrine carcinoma